Review Antimalarial Compounds Isolated from Plants Used In

Review

JPP 2009, 61: 1401–1433 ß 2009 The Authors Received April 7, 2009 Antimalarial compounds isolated from plants used in Accepted June 9, 2009 traditional medicine DOI 10.1211/jpp/61.11.0001 ISSN 0022-3573 Joanne Beroa, Michel Fre´ de´ richb and Joe¨ lle Quetin-Leclercqa

aUniversite´ catholique de Louvain, Louvain Drug Research Institute, Analytical Chemistry, Drug Analysis and Pharmacognosy Unit, Brussels and bUniversity of Lie` ge, Natural and Synthetic Drugs Research Center, Laboratory of Pharmacognosy, Lie` ge, Belgium

Abstract Objectives This review covers the compounds with antiplasmodial activity isolated from plants published from 2005 to the end of 2008, organized according to their phytochemical classes. Details are given for substances with IC50 values £ 11 mM. Key findings Malaria is a major parasitic disease in many tropical and subtropical regions and is responsible for more than 1 million deaths each year in Africa. The rapid spread of resistance encourages the search for new active compounds. Nature and particularly plants used in traditional medicine are a potential source of new antimalarial drugs as they contain molecules with a great variety of structures and pharmacological activities. Summary A large number of antimalarial compounds with a wide variety of structures have been isolated from plants and can play a role in the development of new antimalarial drugs. Ethnopharmacological approaches appear to be a promising way to find plant metabolites that could be used as templates for designing new derivatives with improved properties. Keywords antiplasmodial; malaria; plant compounds; Plasmodium falciparum; traditional medicine

Introduction Malaria is a parasitic disease caused by Plasmodium species transmitted from the blood of an infected person and passed to a healthy human by a female Anopheles mosquito. There are four types of human malaria and Plasmodium falciparum is responsible for the most severe cases, and so most studies have evaluated the activity of compounds on this species. Malaria affects 350–500 million people per year worldwide and is responsible for 1.1 million deaths per year. In many parts of the world the parasites have developed resistance to a number of antimalarials such as chloroquine and derivatives, the most widely used treatment for malaria, and so there is an urgent need to discover new compounds with an original mode of action. Plants commonly used in traditional medicine are a source of active new compounds. For example, artemisinin isolated from Artemisia annua and used in China to treat malaria is a sesquiterpene lactone prescribed in combination therapies to fight chloroquino-resistant P. falciparum. In this review, all new active metabolites isolated from plants used in traditional medicine to treat malaria are described and organised according to their phytochemical classes. All the activities described were determined in vitro on P. falciparum strains, unless otherwise specified, and bio-guided fractionation was also based on this antimalarial test. Activities were assessed on different strains, among which are chloroquine sensitive (NF54, NF54/64, 3D7, D6, F32, D10, HB3, FCC1-HN, Ghana), chloroquine resistant (FcB1, W2, FCM29, BHz26/86, Dd2, EN36, ENT30, FCR3, FCR-3/A2) and/or multidrug resistant (K1, TM91C235) strains, to find effective compounds against resistant malaria. We considered that those having an Correspondence: J. Bero, IC50 £ 11 mM may have some interest for further development, while those with lower Catholic University of Louvain, activity were less interesting. We only give structures for promising compounds, the others Analytical Chemistry, Drug are cited in tables. As reviews already exist for compounds published before 2005,[1–7] Analysis and Pharmacognosy we focused on those published from 2005 to the end of 2008. Some examples of recent Unit, Avenue E. Mounier, [8] 72, B-1200 Brussels, Belgium. natural antiplasmodial compounds are also cited in Mambu and Grellier and, more [9] E-mail: [email protected] recently, in Kaur et al. Author Copy: This article was published by the Pharmaceutical Press, which has granted the author permission to distribute this material for personal or professional (non-commercial) use only, subject to the terms and conditions of the Pharmaceutical Press Licence to Publish. Any substantial or systematic reproduction, re-distribution, re-selling, 1401 sub-licensing or modification of the whole or part of the article in any form is expressly forbidden. 1402 Journal of Pharmacy and Pharmacology 2009; 61: 1401–1433

Phenolic derivatives stricta Roxb. (Leguminosae) roots and Erythrina subum- Flavonoid derivatives brans Merr. (Leguminosae) stems led to the isolation of two 24 25 Bioassay-guided fractionation of the ethyl acetate extract of pterocarpans, erybraedin A ( ) and erystagallin A ( ), and 26 the leaves of Piptadenia pervillei Vatke (Leguminosae) led one flavanone, 5-hydroxysophoranone ( ). All of them exhibited reasonable antiplasmodial activity against K1 with to the isolation of two phenolic compounds: (+)-catechin 5- [18] IC50 = 8.7, 9.0 and 5.3 mM, respectively. Vogelin C (27) gallate (1) and (+)-catechin 3-gallate (2). Compounds 1 and 2 and lespedezaflavanone B (28) were isolated from the bark of displayed high activity, with IC50 values of 1.2 mM and Erythrina subumbrans Merr. (Leguminosae) and possessed 1.0 mM (FcB1), respectively, and no significant cytotoxi- [10] antiplasmodial activity against K1 with IC50 values of 6.6 city. New secondary metabolites were isolated from the [19] and 9.1 mM, respectively. A known compound, 6-pre- root extract of Bauhinia purpurea L. (Leguminosae). Among nylapigenin (29), was isolated from Cannabis sativa L. the isolated metabolites, a flavanone exhibited moderate (Cannabaceae) and displayed notable antimalarial activity antimalarial activity, demethoxymatteucinol (3) (IC50 = against D6 and W2 with IC50 values of 6.7 and 4.8 mM, m [11] 9.5 M against K1). Phytochemical investigation of the respectively.[20] The 80% ethanol extract from the outer bark stem bark and root bark of Friesodielsia obovata (Benth.) of Ochna integerrima Lour. (Merr.) (Ochnaceae) led to Verdc. (Annonaceae) also afforded demethoxymatteucinol isolation of a biflavanone (30) that had not been found 3 ( ), which possessed weak antiplasmodial activity, with previously from a natural plant source and is a potent m IC50 = 34.1 and 29.9 M against K1 and NF54, respec- antimalarial ingredient against K1 (IC50 = 157 nM). The [12] tively. Investigation of the chemical constituents of the stereoisomer of 30 (31) was also isolated from this plant but root bark of Artocarpus rigidus Blume subsp. rigidus its activity was significantly lower than that of 30 (IC50 = [21] (Moraceae) led to the isolation of two known flavonoids, 10.2 mM). The antiplasmodial activity of five natural artonin F (4) and cycloartobiloxanthone (5), which exhibited biflavonoids was estimated on K1. Lanaroflavone (32) antiplasmodial activity against K1 (4.8 mM and 8.5 mM, isolated from the aerial parts of Campnosperma panamensis respectively).[13] Two new prenylated flavones, artocarpones Standl. (Anacardiaceae) showed the highest antiplasmodial A(6) and B (7) (IC50 = 0.12 and 0.18 mM, respectively), and activity (IC50 = 0.48 mM) and exhibited a high selectivity seven known prenylated flavonoids, including artonin A (8) index value (SI = 159), indicating selective antiplasmodial (IC50 = 0.55 mM), cycloheterophyllin (9) (IC50 = 0.02 mM), activity. Ginkgetin (33), isoginkgetin (34), bilobetin (35) artoindonesianin R (10) (IC50 = 0.66 mM), heterophyllin and sciadopitysin (36) isolated from the leaves of Ginkgo (11) (IC50 = 1.04 mM), heteroflavanone C (12) and artoin- biloba L. (Ginkgoaceae) showed antiplasmodial activity donesianin A-2 (13) (IC50 = 1.31 mM) were isolated from the (IC50 = 2.0, 3.5, 6.7 and 1.4 mM with SI = 4.1, 3.2, 4.0 and 49, respectively).[22,23] A new biflavanone, ent-naringeninyl- stem bark of Artocarpus champeden Spreng. (Moraceae). 0 The isolated compounds were tested for their inhibitory (I-3a,II-8)-4 -O-methylnaringenin (37) was isolated from the activity against 3D7. All possessed interesting activity with root bark of Garcinia livingstonei T.Anderson (Clusiaceae) inhibitory concentrations from 0.001 to 1.31 mM. Compound collected in Tanzania. This compound showed reasonable m [24] 12 was the most potent with an IC50 of 1 nM. The inhibitory activity against Ghana strain (IC50 = 6.7 M). Phyto- activity of these flavonoid derivatives supports the traditional chemical re-examination of the aerial exudates of Polygonum use of the dried stem bark of A. campeden as an antimalarial senegalense Meisn. (Polygonaceae) forma senegalense 38 39 drug.[14] Antitubercular and antimalarial activity-guided resulted in the isolation of two chalcones ( and ) active, respectively, with an IC50 of 3.1 mM on D6 and 2.4 mM on study of the dichloromethane extract of the roots of m m [25] Artocarpus altilis (Parkinson) Fosberg (Moraceae) led to W2, and 14.0 M on D6 and 9.5 M on W2. The bioassay- guided purification of an n-hexane extract from the leaves of the isolation of nine prenylated flavones, including cycloar- Piper hostmannianum C.DC. var. berbicense (Piperaceae) tocarpin (14), artocarpin (15), chaplashin (16), morusin (17), led to the isolation of four monoterpenes or prenyl- cudraflavone B (18), artonin E (19) and artobiloxanthone substituted dihydrochalcones as well as known compounds. (20). All compounds exhibited antiplasmodial activity (–)-Methyllinderatin (40) and linderatone (41) exhibited against K1 with IC50 values of 9.9, 6.9, 7.7, 4.5, 5.2, 6.4 [15] moderate antiplasmodial activity with IC50 values of 5.6 and 6.9 mM, respectively. Ethyl acetate extract from the and 5.3 mM (40) and 10.3 and 15.1 mM (41), respectively, stem bark of Erythrina fusca Lour. (Leguminosae) showed against F32 and FcB1. The activity of 40 was confirmed in 21 antimalarial activity against K1, and lonchocarpol A ( ) vivo against Plasmodium vinckei petteri in mice (80% isolated from that extract showed notable antimalarial reduction of parasitemia) at a dose of 20 mg/kg per day m activity (IC50 = 3.9 M). However, two others flavonoids intraperitonally.[26] A prenylated chalcone, medicagenin isolated from the same sample did not show any activity, (42), was isolated from Crotalaria medicagenia Lam. even though these compounds possessed prenylated substitu- (Leguminosae). Antimalarial activity was evaluated against [16] tion. Isoflavonoids and flavonoids were isolated from the NF-54 and medicagenin exhibited 100% inhibition of root bark and the stem bark of Erythrina sacleuxii Hua schizont maturation at a concentration of 2 mg/ml.[27] A (Leguminosae). The two most active against D6 and W2 prenylated chalcone, bartericin A (43), and three known 0 were 5 -prenylpratensein (22, IC50 on D6 = 6.3 mM and IC50 natural products, stipulin (44), 4-hydroxylonchocarpin (45) on W2 = 8.7 mM) and shinpterocarpin (23,IC50on and kanzonol B (46) were isolated from the twigs of [17] D6 = 6.6 mM and IC50 on W2 = 8.3 mM). Phytochemical Dorstenia barteri var. subtriangularis (Engl.) Hijman & C.C. investigation of the hexane and CH2Cl2 extracts of Erythrina Berg (Moraceae). These compounds were evaluated against

W2 and found to be moderately active (IC50 = 2.2, 5.1, 3.4 Stilbenes [28] and 9.6 mM,respectively). Bioassay-directed fractionation A new stilbene glycoside, piceid-(1!6)-b-D-glucopyrano- of the EtOAc extract of the stem bark of Hintonia latiflora side (60), was isolated from the MeOH extract of the leaves (Sesse´ & Moc. ex DC.) Bullock (Rubiaceae), using the in-vitro of Parthenocissus tricuspidata Planch. (Vitaceae) together 16-h and the in-vivo 4-day suppression tests on Plasmodium with three known compounds, piceid (IC50 = 13.2 mM), berghei schizont numbers, led to the isolation of the new longistylin A (IC50 = 34.3 mM) and longistylin C (IC50 = 0 0 5-O-b-D-glucopyranosyl-7,4 -dimethoxy-3 -hydroxy-4-phenyl- 19.2 mM). The antiplasmodial activity of isolated compounds coumarin, along with the known 5-O-b-D-glucopyranosyl-7- was determined in vitro against D10. Among the compounds 0 0 methoxy-3 ,4 -dihydroxy-4-phenylcoumarin. Both compounds isolated, 60 was the best inhibitor with an IC50 value [36] suppressed the development of P. berghei schizonts with of 5.3 mM. Compound 60 was tested in vivo against IC50 values of 24.7 and 25.9 mM, respectively, and the latter P. berghei in mice intraperitoneally and exhibited significant compound suppressed the development of schizonts by blood schizontocidal activity in 4-day early infection, in 70.8% at an oral dose of 40 mg/kg in the in-vivo assay.[29] preventive and curative treatment, with chemosuppression Figure 1 shows the flavonoid derivatives with moderate of 59 and 44% at 5 mg/kg per day, respectively, and an or promising activity in vitro against various strains of LD50 > 500 mg/kg.[37] A stilbene glycoside was isolated P. falciparum. from an n-butanol-soluble fraction of the root of Pleur- opterus ciliinervis Nakai (Polygonaceae). The compound Xanthones was identified as (E)-resveratrol-3-O-a-L-rhamnopyranosyl- The methanol extract of the stem bark of Allanblackia (1-2)-b-D-xylopyranoside (61). It showed only moderate monticola Mildbr. (Clusiaceae) resulted in the isolation of a cytotoxicity and antimalarial activity against D10 with an [38] new prenylated xanthenedione, designated as allanxanthone C IC50 of 3.9 mM. Compound 61 was also found to have (47), together with the known compounds norcowanin (48), moderate antimalarial activity in vivo when tested against mangostin (49) and tovophyllin A (50). Compounds were P. berghei in mice intraperitoneally. It possessed useful assayed for their antiplasmodial activity and for their blood schizontocidal effects when used at doses that cause cytotoxicity. Three of these compounds (47–49)werefound no marked toxicity in mice.[39] to be active against Plasmodium: 47,IC50onFcM29= Figure 3 shows stilbenes with moderate or promising 1.3 mM andIC50onF32=6.9mM; 48, not tested on FcM29 activity in vitro against various strains of P. falciparum. andIC50onF32=6.3mM; 49,IC50onFcM29=4.1mM and IC50 on F32 = 7.8 mM, and also showed weak cytotoxicity Coumarins against human melanoma A375 cells.[30] Tovophyllin A (50) Biologically guided fractionation of the methanolic extract of was the most interesting with promising antimalarial activity the roots of Zanthoxylum flavum Vahl. (Rutaceae) led to the (IC50onFcM29=0.7mM andIC50onF32=20.3mM)and isolation of isoimperatorin (62) which displayed IC50 values [31] [40] relatively low cytoxicity. A new prenylated xanthone, 5-O- of 5.5 and 2.7 mM against D6 and W2, respectively. A new methylcelebixanthone (51), together with a known compound, coumarinolignan was isolated from a sample of Grewia cochinchinone C (52), were isolated from roots of Cratoxylum bilamellata Gagnep. (Tiliaceae), grewin (63), which dis- cochinchinense Blume (Clusiaceae). Compounds 51 and played antimalarial activity against D6 and W2 (IC50 52 exhibited antimalarial activity against K1 with IC50 values 11.2 mM and 5.5 mM, respectively) without significant [41] of 8.9 and 6.3 mM, respectively. IC50 values for cytotoxicity cytotoxicity. The compound 1-O-galloyl-6-O-luteoyl-a- were within the range of 5.6 mM for 52. No cytotoxicity was D-glucose (64) with an IC50 value of 2.21 mM (FCR3) was observed with 51.[32] A xanthone derivative, gaboxanthone isolated from the boiled aqueous extract of the whole plant of (53), was isolated from the seed shells of Symphonia Phyllanthus niruri L. (Euphorbiaceae).[42] globulifera L.f. (Clusiaceae), together with known com- Figure 4 shows coumarins with moderate or promising pounds, symphonin (54) and globuliferin (55). The antiplas- activity in vitro against various strains of P. falciparum. modial activity of the phenolic compounds was evaluated against W2. Compounds 53–55 gave IC50 values of 3.5, 1.3 Lignans [33] and 3.9 mM,respectively. The whole plant of Swertia alata From the hexane extract of Holostylis reniformis Duch. Royle ex D.Don (Gentianaceae) was investigated and three (Aristolochiaceae), five lignans were isolated: (70R,8S,80R)- xanthones, swertiaperennine, swertianin and decussatin, were 4,5-dimethoxy-30,40-methylenodioxy-2,70-cyclolignan-7-one 0 0 0 0 isolated and tested for antimalarial activity. The results (65) (IC50 = 0.26 mM), (7 R,8S,8 R)-3 ,4,4 ,5-tetramethoxy- 0 0 0 indicated that all xanthones possessed superior IC50 values 2,7 -cyclolignan-7-one (66) (IC50 = 0.32 mM), (7 R,8R,8 S)- 0 0 0 at 50 mM. However, swertiaperennine was tested in vivo in the 3 ,4,4 ,5-tetramethoxy-2,7 -cyclolignan-7-one (67) (IC50 = 0 0 0 0 0 P. berghei test model and reduced parasitemia by 17.60% at a 0.20 mM), (7 R,8S,8 S)-3 ,4,4 ,5-tetramethoxy-2,7 -cyclo- [34] 0 0 0 0 dose of 10 mg/kg. A new compound, garciniaxanthone lignan-7-one (68) (IC50 = 0.63 mM) and (7 R,8S,8 S)-3 ,4 - (56), was isolated from the roots of Garcinia polyantha Oliv. dimethoxy-4,5-methylenodioxy-2,70-cyclolignan-7-one (69) (Clusiaceae), in addition to three known compounds, smeath- (IC50 = 8.00 mM). Most compounds possessed high antiplas- xanthone A (57), smeathxanthone B (58) and chefouxanthone modial activity against BHz26/86 and low toxicity on hepatic (59). They exhibited antimalarial activity against NF54 with cells. Therefore, these compounds are potential candidates for [35] [43] IC50 values ranging from 2.5 to 4.1 mM. the development of antimalarial drugs. Seven tetrahydro- Figure 2 shows xanthones with moderate or promising furan lignans isolated from Nectandra megapotamica Mez activity in vitro against various strains of P. falciparum. (Lauraceae) were evaluated for their antimalarial activity.

OH HO OH

HO O HO O O O OH O

OR2 OR OH O O 1 OH OH 3 4 OH Ga 5 HO OCH O 3 HO OH 5 5 OH HO O 1.R1 Ga, R2 H 5 5 OH 2.R1 H, R2 Ga HO O O HO OH OH O

O O OH O 6 O 7

OH H3CO OCH3 OH O OH 5 HO O OH O O

O OH O HO OH OH O

O O O 9 10 OH OCH OH O 3 H3CO OCH3 8 HO O HO O O OCH3 HO OH OH O OH O O O OH 12 13

OH OH OH O H CO O 3 H CO O 11 3 OH O OH OH O OH O H3CO O OH

O 15 16 OH O HO OH HO OH

14 O O O O

OH O OH O

17 18

OH HO OH OH HO O HO OH O O OH O O OH O OH O 20 21 OH O 19

Figure 1 Flavonoid derivatives with moderate or promising activity in vitro against various strains of P. falciparum

HO O OH HO O OH OCH3 O OH OH O HO O O H O H 22 O H 25 OCH3 23 O OH 24 OH

HO O HO O OH OH OH O OH O HO O 26 OH 27 OH O OH OH OH 28 HO O

HO O H O HO O H H O OH O H H 29 OH O H H O OH O H O OH

OH O OH O O 30 31 HO O HO OH

32 OH O OH R2 R3 OR2 HO O R1 O OH O OR4 OH O 5 5 5 O HO O 38. R1 R2 OCH3, R3 OH 39. R 5 H, R 5 OH, R 5 OCH R O O 1 2 3 3 3 O 37 R1O OH OH O OH O 5 5 5 5 OH 33. R1 CH3, R2 H, R3 CH3, R4 CH3 34. R 5 H, R 5 CH , R 5 H, R 5 CH 15 25 3 53 54 3 HO 35. R1 H, R2 H, R3 H, R4 CH3 5 5 5 5 36. R1 H, R2 CH3, R3 CH3, R4 CH3

OH O HO O H 42 H O OH OH O

OH O 41 HO HO OH 40

O OH OH O

43 HO O HO OH OH O 45 OH O OH O 44 46

Figure 1 (Continued)

O OH O OH O O OH H3CO HO HO O OH HO O OH HO O OH 49 47 48 O OH O OH O H3CO O OH O O HO O OH H3CO O 50 HO O

OCH3 51 52 O OH O OH H3CO O OH H CO 3 H3CO H3CO O O H3CO O OH OH H3CO O O OH OH 53 54 55

OH O OH OH O OH OH O OH

O OCH3 O O OH OH O OH 58 OH OH O OH O 57 56

O OH OH

Figure 2 Xanthones with moderate or promising activity in vitro against various strains of P. falciparum

Among the evaluated compounds, calopeptin (70) displayed moderate activity, with IC50 values of 10.7 mM (D6 clone) and [44] 11.0 mM (W2 clone), and no cytotoxicity. Bioassay-directed OH OH fractionation of the antimalarial active CHCl3 extract of the dried stems of Rourea minor (Gaertn.) Aubl. (Connaraceae) HO HO liana led to the isolation of rourinoside (71). This lignan showed activity with an IC50 value of 3.7 mM against D6 and [45] 2.1 mM against W2 strains. HO O OH O OH Figure 5 shows lignans with moderate or promising OH OH O O activity in vitro against various strains of P. falciparum. O O OH OH OH Tannins OH OH Partitioning of extracts of Punica granatum L. (Lythraceae) O OH O led to the isolation of ellagic acid, gallagic acid (72), 60 61 OH punicalin and punicalagin (73). Gallagic acid and punicalagin exhibited moderate antiplasmodial activity against D6 Figure 3 Stilbenes with moderate or promising activity in vitro against (IC50 of 10.9 and 10.6 mM) and W2 clones (IC50 of 7.5 and [46] various strains of P. falciparum 8.8 mM).

OH OH O O O HO OH O O O

HO O O O O HO HO OCH3 62 O O 63 HO OH OH HO OH

HO O O OH 64

Figure 4 Coumarins with moderate or promising activity in vitro against various strains of P. falciparum

O O O O H3CO H CO H3CO H3CO 3

H3CO H3CO H3CO H3CO

65 68 66 67 O OCH OCH3 OCH3 3 O OCH OCH3 OCH3 3 O OH

O OCH3 O O O H3CO O OCH3 70 O OCH3

OCH3 HO OH OCH3 OGlu 69 H3CO 71

Figure 5 Lignans with moderate or promising activity in vitro against various strains of P. falciparum

[49] Figure 6 shows tannins with moderate or promising K1 (IC50 = 0.67 mM). A new bischromone, chrobisiamone activity in vitro against various strains of P. falciparum. A(78), was isolated from the leaves of Cassia siamea Lam. (Leguminosae). Compound 78 displayed antiplasmodial [50] activity against 3D7 with an IC50 of 5.6 mM. A new Other phenolic derivatives cannabichromanone A derivative was isolated along with the The petroleum ether extract of Viola websteri Hemsl. known cannabichromanone C (79) from Cannabis sativa L. (Violaceae) was investigated and the main antiplasmodial (Cannabaceae). Cannabichromanone A showed mild anti- compound was 6-(80Z-pentadecenyl)-salicylic acid (74) with malarial activity against D6 and W2 clones with IC50 values [47] an IC50 of 10.1 mM (D10). Dictyochromenol (75) and of 11.1 and 11.4 mM, respectively, while cannabichromanone 0 0 [51] a known compound, 2 E,6 E 2-farnesyl hydroquinone (76) C had IC50 values of 13.1 and 9.4 mM, respectively. obtained from the petroleum ether extract of the whole plant of Guttiferone A (80) was isolated from the seed shells of Piper tricuspe C.DC. (Piperaceae) showed antimalarial Symphonia globulifera L.f. (Clusiaceae). The antiplasmodial activity against FcB1 with IC50 values of 9.58 and 1.37 mM activity of compound 80 was evaluated against W2 and [48] [33] while the selectivity index suggests their high toxicity. gave an IC50 value of 3.2 mM. Isoxanthochymol (81) 4-Nerolidylcatechol (77), isolated from the roots of Potho- was isolated from the roots of Garcinia polyantha Oliv. morphe peltata (L.) Miq. (Piperaceae) presented significant (Clusiaceae) and exhibited antimalarial activity against NF54 [35] inhibition (more active than quinine and chloroquine) against with an IC50 of 2.2 mM.

Figure 7 shows other phenolic derivatives with moderate Table 1 gives the tested phenolic derivatives presenting or promising activity in vitro against various strains of low or no activity in vitro against various strains of P. falciparum. P. falciparum.[12,13,16,17,25,26,28,29,32,34,37,40–42,47,48,50–66]

HO OH OH OH O HO HO O OH OH OH HO HO O O OH OH HO OH OH HO O O HO O HO O O OH O OH O OH O

O 72 O O O O O OH O

HO OH

73 HO OH HO OH

Figure 6 Tannins with moderate or promising activity in vitro against various strains of P. falciparum

COOH 74 75 OH

OH 76 77 OH OH HO O O OH O O OH H

O O O O O 78 O 79

O OH HO O HO O O HO O O O OH 81 80

Figure 7 Other phenolic derivatives with moderate or promising activity in vitro against various strains of P. falciparum

Table 1 Phenolic derivatives presenting low or no activity in vitro against various strains of P. falciparum

Compound Plant Family IC50 (mM) Reference no.

Lawinal Friesodielsia obovata (Benth.) Verdc. Annonaceae 27.5 (K1) 12 119.1 (NF54) 20,40-Dihydroxy-30-(2-hydroxybenzyl)- Ellipeiopsis cherrevensis Annonaceae 18.9 (K1) 52 60-methoxychalcone (Pierre ex Finet & Gagnep.) R.E.Fr. Syringic acid Commiphora opobalsamum Engl. Burseraceae 17.7 (D6) 53 16.2 (W2) Cannabichromanone A Cannabis sativa L. Cannabaceae 11.1 (D6) 51 11.4 (W2) Celebixanthone Cratoxylum cochinchinense Blume Clusiaceae 14.3 (K1) 32 b-Mangostin Cratoxylum cochinchinense Blume Clusiaceae 16.9 (K1) 32 1,5-Dihydroxy-3-methoxy-4- Chrysochlamys tenuis Hammel Clusiaceae 31 (W2) 54 isoprenylxanthone 1,3,7-Trihydroxy-2,4- Chrysochlamys tenuis Hammel Clusiaceae 20 (W2) 54 diisoprenylaxnthone Toxyloxanthone A Chrysochlamys tenuis Hammel Clusiaceae 16 (W2) 54 Combretastatin D-3 Getonia floribunda Roxb. Combretaceae – 55 Combretastatin D-4 Getonia floribunda Roxb. Combretaceae – 55 3,5-Di-O-galloylquinic acid Sloanea rhodantha (Baker) Elaeocarpaceae 31.7 (HB3) 56 Capuron var. rhodantha 23.6 (FcM29) 1,6-Di-O-galloyl glucopyranoside Sloanea rhodantha (Baker) Elaeocarpaceae 35.5 (HB3) 56 Capuron var. rhodantha 15.7 (FcM29) 3,4,5-Tri-O-galloylquinic acid Sloanea rhodantha (Baker) Elaeocarpaceae 35.3 (HB3) 56 Capuron var. rhodantha 23.1 (FcM29) 1,2,3,6-Tetra-O-galloyl glucopyranoside Sloanea rhodantha (Baker) Elaeocarpaceae 20.2 (HB3) 56 Capuron var. rhodantha 20.6 (FcM29) 3-O-b-D-Glucopyranosyl-(2!1)-O- Phyllanthus niruri L. Euphorbiaceae 18.5 (FCR3) 42 b-D-xylopyranoside b-Glucogallin Phyllanthus niruri L. Euphorbiaceae 14.6 (FCR3) 42 (E)-3-(4-Methoxy-phenyl)-2-phenyl- Croton lobatus L. Euphorbiaceae 19.1 (K1) 57 acrylic acid Swertiaperennine Swertia alata Royle ex D.Don Gentianaceae >50 34 Swertianin Swertia alata Royle ex D.Don Gentianaceae >50 34 Decussatin Swertia alata Royle ex D.Don Gentianaceae >50 34 Luteolin Satureja parvifolia (Phil.) Epling Lamiaceae 22.3 (K1) 58 Lupinifolin Erythrina fusca Lour. Leguminosae 30.8 (K1) 16 Citflavanone Erythrina fusca Lour. Leguminosae 14.8 (K1) 16 8-Prenyldaidzein Erythrina fusca Lour. Leguminosae 12.1 (K1) 16 5-Deoxy-30-prenylbiochanin Erythrina sacleuxii Hua Leguminosae 17.6 (D6) 17 22.5 (W2) Corylin Erythrina sacleuxii Hua Leguminosae 16.6 (D6) 17 19.7 (W2) Erysubin F Erythrina sacleuxii Hua Leguminosae 12.0 (D6) 17 12.8 (W2) 30-Prenylbiochanin A Erythrina sacleuxii Hua Leguminosae 23.7 (D6) 17 28.4 (W2) 7-Demethylrobustigenin Erythrina sacleuxii Hua Leguminosae 27.2 (D6) 17 31.7 (W2) 50-Formylpratensein Erythrina sacleuxii Hua Leguminosae 21.7 (D6) 17 27.9 (W2) 2,3-Dehydrokeivetone Erythrina sacleuxii Hua Leguminosae 15.1 (D6) 17 12.7 (W2) Prostratol C Erythrina sacleuxii Hua Leguminosae 17.6 (D6) 17 19.8 (W2) Saclenone Erythrina sacleuxii Hua Leguminosae 24.2 (D6) 17 22.6 (W2) 2,3-Dihydro-7-demethylrobustigenin Erythrina sacleuxii Hua Leguminosae 28.0 (D6) 17 31.8 (W2) (3R)-7-Hydroxy-30,40-dimethoxyisofla- Colutea istria Mill. Leguminosae >50 (D6, W2) 59 van-20,50-quinone 6,30-Dihydroxy-7,40- Colutea istria Mill. Leguminosae >50 (D6, W2) 59 dimethoxyisoflavone (Continued)

Table 1 (Continued)

Compound Plant Family IC50 (mM) Reference no.

20-Methoxy-40,50-methylenedioxy-7,8-[2- Millettia puguensis J.B.Gillett Leguminosae >50 60 (1-methylethenyl)furo]isoflavone (–)-Maackiain Millettia puguensis J.B.Gillett Leguminosae >50 60 6,7-Dimethoxy-30,40- Millettia puguensis J.B.Gillett Leguminosae >50 60 methylenedioxyisoflavone 7,20-Dimethoxy-40,50- Millettia puguensis J.B.Gillett Leguminosae >50 60 methylenedioxyisoflavone 5-Acetonyl-7-hydroxy-2- Cassia siamea Lam. Leguminosae 19.4 (3D7) 50 methylchromone Anhydrobarakol Cassia siamea Lam. Leguminosae 36.4 (3D7) 50 7-Demethylartonol E Artocarpus rigidus Blume subsp. rigidus Moraceae 18.0 (K1) 13 Bartericin B Dorstenia barteri var. subtriangularis Moraceae 19.3 (W2) 28 (Engl.) Hijman & C.C.Berg Isobavachalcone Dorstenia barteri var. subtriangularis Moraceae 19.0 (W2) 28 (Engl.) Hijman & C.C.Berg Talaumidin Pycnanthus angolensis (Welw.) Warb. Myristicaceae 60.5 (Dd2) 61 5-Galloylquercetin-3-O-R-L- Calycolpus warscewiczianus O.Berg Myrtaceae 14.5 (W2) 62 arabinofuranoside 20,60-Dihydroxy-40- Piper hostmannianum Piperaceae 12.7 (F32) 26 methoxydihydrochalcone C.DC. var. berbicense 16.9 (FcB1) 3-Farnesyl-p-hydroxybenzoic acid Piper tricuspe C.DC. Piperaceae 29.78 (FcB1) 48 Polygohomoisoflavanone Polygonum senegalense Polygonaceae 19.2 (D6) 25 Meisn. forma senegalense 18.2 (W2) 2-Propen-1-one,1-(2,4-dihydroxy-3, Polygonum senegalense Polygonaceae 16.6 (D6) 25 6-dimethoxyphenyl)-3-phenyl- Meisn. forma senegalense 17.8 (W2) 2-Propen-1-one, 1-(2-hydroxy-4, Polygonum senegalense Polygonaceae 15.7 (D6) 25 6-dimethoxyphenyl)-3-phenyl- Meisn. forma senegalense 11.3 (W2) 1-Propanone, 1-(2,6-dihydroxy-4-meth- Polygonum senegalense Polygonaceae 23.5 (D6) 25 oxyphenyl)-3-phenyl- Meisn. forma senegalense 22.8 (W2) 1-Propanone, 1-(2,6-dihydroxy-3, Polygonum senegalense Polygonaceae 11.8 (D6) 25 4-dimethoxyphenyl)-3-phenyl- Meisn. forma senegalense 12.9 (W2) 4H-1-Benzopyran-4-one,2,3-dihydro- Polygonum senegalense Polygonaceae 16.3 (D6) 25 5-hydroxy-7-methoxy-2-phenyl- Meisn. forma senegalense 21.8 (W2) 2-Propen-1-one,1-(2,4-dihydroxy- Polygonum senegalense Polygonaceae 14.0 (D6) 25 6-methoxyphenyl)-3-phenyl- Meisn. forma senegalense 9.5 (W2) Quercetin Morinda morindoides (Baker) Rubiaceae 18.2 (K1) 63 Milne-Redh. 0 5-O-b-D-Glucopyranosyl-7,4 - Hintonia latiflora Rubiaceae 24.7 (P. berghei)29 dimethoxy-30-hydroxy-4- (Sesse´ & Moc. ex DC.) Bullock phenylcoumarin 5-O-b-D-Glucopyranosyl-7-methoxy- Hintonia latiflora Rubiaceae 25.9 (P. berghei)29 30,40-dihydroxy-4-phenylcoumarin (Sesse´ & Moc. ex DC.) Bullock Bipinnatones A Boronia bipinnata Lindl. Rutaceae 64 (Hbase II assay) 64 Bipinnatones B Boronia bipinnata Lindl. Rutaceae 51 (Hbase II assay) 64 Bergapten Zanthoxylum flavum Vahl. Rutaceae 21.8 (W2) 40 Syringaldehyde Vepris uguenensis Engl. Rutaceae 71.4 (3D7) 65 117.6 (FcM29) Greveichromenol Harrisonia perforata Merr. Simaroubaceae 38.3 (K1) 66 Nitidanin Grewia bilamellata Gagnep. Tiliaceae 21.2 (D6) 41 18.4 (W2) 6-(80Z,110Z,140Z-Heptadecatrienyl)- Viola websteri Hemsl. Violaceae 13.3 (D10) 47 salicylic acid Piceid Parthenocissus tricuspidata Planch. Vitaceae 13.2 (D10) 37 Longistylin A Parthenocissus tricuspidata Planch. Vitaceae 34.3 (D10) 37 Longistylin C Parthenocissus tricuspidata Planch. Vitaceae 19.2 (D10) 37

Quinones non-cannabinoid constituent was isolated from Cannabis Primin (82), a natural benzoquinone occurring in Primula sativa L. (Cannabaceae) namely 5-acetoxy-6-geranyl-3-n- obconica Hance. (Primulaceae), was investigated for its pentyl-1,4-benzoquinone (83), which displayed notable antiprotozoal potential. Compound 82 showed moderate antimalarial activity against D6 and W2 clones with IC50 [67] [20] activity against K1 with an IC50 of 10.9 mM. A new values of 7.5 and 7.0 mM, respectively. New secondary

Author Copy: This article was published by the Pharmaceutical Press, which has granted the author permission to distribute this material for personal or professional (non-commercial) use only, subject to the terms and conditions of the Pharmaceutical Press Licence to Publish. Any substantial or systematic reproduction, re-distribution, re-selling, sub-licensing or modification of the whole or part of the article in any form is expressly forbidden. Antimalarial plant compounds Joanne Bero et al. 1411 metabolites were isolated from the root extract of Bauhinia of Cyperus articulatus L. (Cyperaceae), exhibited antiplas- purpurea L. (Leguminosae). Among the isolated metabolites, modial properties (IC50 = 4.53 and 0.64 mM against NF54 [77] two compounds exhibited antimalarial activity against K1, and IC50 = 8.14 and 1.15 mM against EN36, respectively). bauhinoxepin I (84) (IC50 = 10.5 mM) and bauhinoxepin J Oncosiphon piluliferum (L.f.) Ka¨llersjo¨ (Asteraceae) is used [11] (85) (IC50 = 5.8 mM). The ethanol extract of Zhumeria traditionally to treat a variety of ailments, mainly fevers. majdae Rech. f. & Wendelbo (Lamiaceae) showed potent Sesquiterpene lactones of the germacranolide and eudesma- antiplasmodial activity. Bioactivity-guided fractionation of nolide types displaying antiplasmodial activity against D10 the extract led to the isolation of 12,16-dideoxy aegyptinone were isolated and identified: sivasinolide (106,IC50= B(86). This compound exhibited antiplasmodial activity 9.8 mM), tatridin A or tavulin (107, IC50 = 1.5 mM) and with IC50 values of 4.4 and 4.7 mM against D6 and W2 tanachin (108, IC50 = 1.5 mM). In addition, the cytotoxic strains, respectively. This compound was further found to effects of the active compounds against Chinese Hamster have mild cytotoxicity towards cancer cell lines Ovarian cells were evaluated and the compounds were found to [68] [78] (IC50 = 15.2–50.6 mM). From the roots of Bulbine be toxic to mammalian cells at similar concentrations. Two frutescens Willd. (Asphodelaceae), the first sulfated phenyl- new helenanolide sesquiterpene lactones, helenalin-[2-(1- anthraquinones were isolated, together with their known hydroxyethyl)acrylate] (109) and helenalin-[2-hydroxyethyl- sulfate-free analogues. Two of them, isoknipholone (87) and 3-methyl)acrylate] (110), as well as one known related sodium 40-O-demethylknipholone 60-O-sulfate (88), presented structure, 11a,13-dihydrohelenalin-[2-(1-hydroxyethyl)acry- promising activity against K1 with an IC50 of 0.28 mM for late] (111), were isolated from an ethyl acetate extract of isoknipholone and an IC50 of 7.9 mM for the sulfated leaves of Vernoniopsis caudate (Drake) Humbert (Asteraceae). phenylanthraquinone.[69] From the roots of the African The three lactones displayed strong antiplasmodial activity plant Bulbine frutescens Willd. (Asphodelaceae), two novel against FcB1, with IC50 values of 1, 0.19 and 0.41 mM, dimeric phenylanthraquinones, joziknipholones A (89) and B respectively. However, these compounds also exhibited con- (90), were isolated. These two compounds exhibited strong siderable cytotoxicity on KB cells (IC50 < 1 mM in each [79] activity against K1 with IC50 values of 164 and 270 nM, case). Leaves and flowers of Artemisia gorgonum Webb respectively.[70] Two compounds, 10-(chrysophanol-70-yl)- (Asteraceae) collected in Fogo, Cape Verde, were phytochemi- 10-(x)-hydroxychrysophanol-9-anthrone (91) and chryslandi- cally investigated and resulted in the isolation of a known cin (92), were isolated from the dichloromethane extract of germacranolide, hanphyllin (112), which exhibited antiplasmo- the roots of Kniphofia foliosa Hochst. (Asphodelaceae). They dial activity with an IC50 of 9.7 mM against FcB1 and was [80] showed good activity against 3D7 with IC50 values of 0.5 weakly cytotoxic to the Vero cell line (IC50 = 111.9 mM). [71] and 1.0 mM, respectively. Glaberianthrone (93), a new Two new sesquiterpene lactones, wedelolides A (113)andB bianthrone, was isolated from the hexane extract of the stem (114), were isolated from the leaves of Wedelia trilobata Hitchc. bark of Psorospermum glaberrimum Hochr. (Clusiaceae) (Asteraceae). The two compounds displayed antimalarial [81] together with known compounds, 3-geranyloxyemodin activity with IC50 values of 4.2 and 9.1 mM,respectively. anthrone (95), 3-prenyloxyemodin anthrone (96), 2-geranyl- A new sesquiterpene lactone as well as two known ones were emodin (97) and bianthrone 1a (94). Their IC50 values were isolated from the dichloromethane fraction of an aqueous extract 2.94, 1.68, 1.98, 5.34 and 2.53 mM, respectively, against the from Vernonia cinerea Less. (Asteraceae). Three compounds, W2 strain.[72] Bazouanthrone (98), a new anthrone deriva- 8a-tigloyloxy-hirsutinolide-13-O-acetate(115), 8a-(4-hydroxy- tive, was isolated from the root bark of Harungana ethacryloyloxy)-hirsutinolide-13-O-acetate (116)andver- madagascariensis Poir. (Clusiaceae), together with known nolide D (117), were active against W2 with IC50 values of [82] compounds, feruginin A (99), harunganin (100), harunganol 3.9, 3.7 and 3.5 mM,respectively. Fractionation of the A(101) and harunganol B (102). All the compounds were dichloromethane extract of the leaves of Vernonia staehelinoides found to be moderately active against W2: 98, IC50 = Mart. ex Baker (Asteraceae) allowed the isolation of two 1.8 mM; 99, IC50 = 5.0 mM; 100, IC50 = 2.7 mM; 101, IC50 = structurally related hirsutinolides. These compounds displayed [73] 3.7 mM; 102, IC50 = 3.7 mM. To discover antimalarial strong antiplasmodial activity against D10 and were less effective substances from plants cultivated in Thailand, 80% EtOH against K1, compound 118,8a-(2-methylacryloyloxy)-3-oxo- extracts from selected plants were screened against K1 strain. 1-desoxy-1,2-dehydrohirsutinolide-13-O-acetate had an Polyalthia viridis Craib (Annonaceae) was found to show IC50 = 0.6 mM on D10 and IC50 = 4.5 mM on K1 and compound notable antimalarial activity. Marcanine A (103) (IC50 = 119,8a-(50-acetoxysenecioyloxy)-3-oxo-1-desoxy-1,2-dehy- [74] 10.5 mM) was identified as its major active constituent. drohirsutinolide-13-O-acetate had an IC50/D10 = 0.5 mM and Figure 8 shows quinones and derivatives with moderate IC50/K1 = 5.5 mM. These two compounds were found to be or promising activity in vitro against various strains of cytotoxic to mammalian Chinese Hamster Ovarian cells at P. falciparum. similar concentrations.[83] Chemical exploration of Camchaya Table 2 gives the tested quinones presenting low calcarea Kitam. (Asteraceae) led to the isolation of eight known or no activity in vitro against various strains of P. falci- sesquiterpene lactones, which exhibited moderate antiplasmodial parum.[11,41,63,75,76] activity against K1, including goyazensolide (120)(IC50= 3.3 mM), lychnophorolide B (122)(IC50=7.2mM), isogoya- Terpenoid compounds zensolide (123)(IC50=4.4mM), isocentratherin (124) Sesquiterpenes (IC50 = 5.6 mM), 5-epi-isogoyazensolide (125)(IC50= 4.4 mM) Two sesquiterpenes, corymbolone (104) and mustakone and 5-epi-isocentratherin (126) (IC50 = 8.0 mM). The most (105), isolated from the chloroform extract of the rhizomes promising was lychnophorolide A (121)withanIC50of

O O O O O H CO HO 3 O O O O 83 O 82 84 O O 85 O HO O O HO O OH O OH OH O OH H O HO HO OCH3 O 86 HO O O 89 OH O OH HO OCH NaO SO OH 3 3 O O HO 87 88 HO OCH3 O O OH OH OH HO O OH OH O OH HO HO O O R 1 OH O OH O H O R OH OH HO HO OCH3 OR 2 OR HO 90 91. R5 H R3 95. R5 Geranyl 92. R5 OH OH O OH 96. R5 Prenyl O O 5 5 5 O 93. R1 Geranyl,R2 Prenyl, R3 H HO 5 5 5 94. R1 Geranyl, R2 H, R3 Geranyl HO OCH OH O OH 3 OH OH O R HO R4 R1 O OH H N O H3C OH O R2 97. R5 Geranyl R3 5 5 5 5 98. R1 Prenyl, R2 Prenyl, R3 OH, R4 H 5 5 5 5 99. R1 H, R2 Prenyl, R3 H, R4 Prenyl 103 5 5 5 5 O 100. R1 H, R2 Prenyl, R3 Prenyl, R4 H 5 5 5 5 101. R1 H, R2 H, R3 Prenyl, R4 Prenyl 5 5 5 5 102. R1 H, R2 H, R3 Prenyl, R4 H

Figure 8 Quinones and derivatives with moderate or promising activity in vitro against various strains of P. falciparum

Table 2 Quinones presenting low or no activity in vitro against various strains of P. falciparum

Compound Plant Family IC50 (mM) Reference no.

Newbouldiaquinone A Newbouldia laevis Seem. Bignogniaceae 78% at 20 mM (NF54) 75 Bauhinoxepin H Bauhinia purpurea L. Leguminosae 11.2 (K1) 11 Rubiadin-1-methyl ether Prismatomeris malayana Ridl. Rubiaceae – 76 Nordamnacanthal Prismatomeris malayana Ridl. Rubiaceae – 76 Damnacanthal Prismatomeris malayana Ridl. Rubiaceae – 76 Chrysarin Morinda morindoides (Baker) Milne-Redh. Rubiaceae 105.4 (NF54/64) 63 Alizarin Morinda morindoides (Baker) Milne-Redh. Rubiaceae 60.4 (NF54/64) 63 2,6-Dimethoxy-1-acetonylquinol Grewia bilamellata Gagnep. Tiliaceae 42.2 (D6) 41 23.0 (W2)

[84] 0.8 mM. Bioactivity-guided isolation of the chloroform isolated from Anthemis auriculata Boiss. (Asteraceae), was [87] fractions of the whole plants of Carpesium rosulatum Miq. evaluated against K1 and had an IC50 of 7.6 mM. (Asteraceae) led to the isolation of a sesquiterpene lactone, Figure 9 shows sesquiterpenes with moderate or promis- ineupatorolide A (127), displaying high antiplasmodial activity ing activity in vitro against various strains of P. falciparum. [85] against D10 with an IC50 of 19 nM. Ineupatorolide A was also found to have potential antimalarial activity in vivo when tested Diterpenes against P. berghei in mice. Compound 127 (2, 5, 10 mg/kg per Geranylgeraniol (129) was isolated from the stems and day, intraperitoneally) exhibited a significant blood schizonto- leaves of Croton lobatus L. (Euphorbiaceae), a medicinal cidal activity in 4-day early infection, preventive and curative plant used in western Africa in traditional folk medicine to cure treatment, with a significant mean survival time comparable with malaria, pregnancy troubles and dysentery. The compound that of the standard drug, chloroquine (5 mg/kg per showed reasonable antiplasmodial activity against K1 with an [57] day). Ineupatorolide A possesses promising antiplasmodial IC50 value of 3.7 mM and good selectivity (SI value > 25). activity that can be exploited in malaria therapy.[86] A new diterpenoid, steenkrotin A (130), was isolated from 4-Hydroxyanthecotulide (128), a linear sesquiterpene lactone an ethanol extract of the leaves of Croton steenkampianus

OH OH OH O O O O O O O O

OH OH OH OH 105 106 104 107 108

H H 5 H H 109. R2 H O O H 111. R 5 O 2 HO HO H O O O O O O HO R2O R2O H O 5 112 110. R2 O H HO H O O 115. R5 H O O HO O HO HO OR H O O OR O 116. R5 O O O O OH H O O HO OR O H 1 127 H3C 117. R5 OH 5 5 113. R Tigloyl, R1 Isobutyroyl 5 5 O 114. R Tigloyl, R1 Methacryloyl O 5 O 120. R O O OR 118. R5 OR O 121. R5 O O OAc O O 119. R5 HO O O O O O 122. R5

O O O O O 5 123. R 5 OR OR 125. R H O O O O O 124. R5 O OH 126. R5 HO O HO O 128 O O

Figure 9 Sesquiterpenes with moderate or promising activity in vitro against various strains of P. falciparum

Gerstner (Euphorbiaceae) and was tested against D10, D6, Dd2 0.24, 0.12, 0.6 and 2.9 mM, respectively. Eighteen diterpenes and W2, showing moderate activity with IC50 values of 15.8, possessed strong activity with IC50 £ 1 mM, with norcaesalpi- [88] >30, 9.4 and 9.1 mM,respectively. nin E (171) and 2-acetoxy-3-deacetoxycaesaldekarine (177) Labdane diterpenoid, 3-deoxyaulacocarpin A (131) was being the most potent.[95,96] In continuity with the previous isolated from the seeds of Aframomum zambesiacum work, a new furanocassane-type diterpene, caesalpinin H K. Schum (Zingiberaceae). It possessed antiplasmodial (183), was isolated from the CH2Cl2 extract of the seed kernels [89] activity against FcB1 with an IC50 of 4.97 mM. Known of Caesalpinia crista L. (Caesalpiniaceae) and showed an IC50 [97] compounds were isolated from the dried fruits of Juniperus value of 5.2 mM against FCR-3/A2. Three new cassane seravschanica Komarov (Cupressaceae) and were tested. furanoditerpenoids were isolated from the EtOAc extract of the Three of them showed promising antimalarial activity: cedrol seed kernels of Caesalpinia bonduc L. Roxb. (Caesalpinia- (132) with IC50 = 265, 1.4 and 10.2 mM; sugiol (133) with ceae). Bonducellpins E–G (184–186) exhibited antimalarial IC50 = 1.6, 3.4 and 1.4 mM; and 12,15-dihydroxylabda-8 activity on K1 strain with IC50 values of 1.6, 5.8 and 3.8 mM, (17),13-dien-19-oic acid (134) with IC50 = 2.2, 4.1 and respectively. None of the compounds were cytotoxic against [90] [98] 4.6 mM against D6, TM91C235 and W2, respectively. any of the tumour cell lines tested. Compound 6a,7b- Vitex rehmannii Gu¨rke (Lamiaceae) contained a labdane diacetoxyvouacapane (187) was isolated from the seeds of diterpene, 12S,16S/R-dihydroxy-ent-labda-7,13-dien-15,16- Bowdichia nitida Spruce ex Benth. (Leguminosae), and olide (135), which exists as an inseparable epimeric mixture. showed promising antiplasmodial activity against 3D7 This mixture exhibited reasonable antimalarial activity (IC50 = 968 nM) and a good selectivity index with regard to [99] against FCR-3 (IC50 = 7.2 mM). However, this was due to cytotoxicity (IC50 > 250 mM). Bioactivity-guided fraction- its cytotoxic properties.[91] ation of the petroleum ether extract of the leaves of Hyptis Bioassay-guided fractionation of a trunk bark extract of suaveolens (L.) Poit. (Lamiaceae), widely used in traditional Laetia procera (Poepp.) Eichler (Flacourtiaceae) led to the medicine, led to the isolation of an abietane-type diterpenoid isolation of six clerodane diterpenoids: casearlucin A (136), endoperoxide, 13a-epi-dioxiabiet-8(14)-en-18-ol (188), dis- casamembrol A (137), laetiaprocerine A–D (138–141). The playing high antiplasmodial activity against D10 [100] diterpenoids exhibited antiplasmodial activity with IC50 (IC50 = 344 nM). values of 0.62, 0.57, 0.58, 4.44, 4.66 and 6.04 mM on F32 Five known abietane diterpenes (189–193) were isolated strain, and 0.54, 0.59, 0.66, 6.08, 5.35, 3.79 and 27.5 mM on from five Plectranthus species (Lamiaceae), namely Plec- FCb1 strain, but most of them were also cytotoxic. Compound tranthus hadiensis C. Chr., Plectranthus lucidus Burch. 138 showed the best selectivity index of 6.8.[92] Bioactivity- ex Benth., Plectranthus ecklonii Benth., Plectranthus guided fractionation of hexane and dichloromethane extracts purpuratus Harv. subsp. purpuratus and Plectranthus of the bark of Casearia grewiifolia Vent. (Flacourtiaceae) purpuratus Harv. subsp. tongaensis. The compounds showed afforded four new clerodane diterpenes, caseargrewiins A–D antiplasmodial activity against FCR-3 (IC50 = 4.6, 5.3, 3.1, (142–145), and two known clerodane diterpenes, rel- 6.0 and 4.7 mM, respectively). However, the cytotoxicity (2S,5R,6R,8S,9S,10R,18S,19R)-18,19-diacetoxy-18,19- profile indicated a low degree of specificity towards the epoxy-6-methoxy-2-(2-methylbutanoyloxy)cleroda-3,13 malaria parasite.[101] A bioassay-guided fractionation of (16),14-triene (146) and rel-(2S,5R,6R,8S,9S,10R,18S,19R)- Juniperus procera Hochst. ex Endl. (Cupressaceae) berries 18,19-diacetoxy-18,19-epoxy-6-hydroxy-2-(2-methylbuta- yielded pure compounds. Among these, abieta-7,13-diene noyloxy)cleroda-3,13(16),14-triene (147). All compounds (194) and ferruginol (195) demonstrated antimalarial activity exhibited antimalarial activity against K1 with IC50 values against D6 and W2 strains with IC50 = 7.0 and 7.4 mM, [93] of 5.5, 3.6, 5.2, 7.9, 6.0 and 6.0 mM, but also cytotoxicity. respectively, for 194 and IC50 = 12.3 and 4.9 mM, respec- A new diterpene, (1S,5S,9S,10S,11R,13R)-1,11-dihydroxy- tively, for 195.[102] pimara-8(14),15-diene (148) was isolated from the dichloro- In 2006, the antimalarial activity of ferruginol (IC50 = methane extract of whole plants of Kaempferia marginata 6.9 mM) isolated from Fuerstia africana T.C.E.Fr. (Lamia- Carey (Zingiberaceae) and had antimalarial activity against ceae) was correlated with cytotoxic activity and, therefore, it [94] [103] K1 (IC50 = 10.5 mM). was not a promising antimalarial candidate. Some 44 cassane- and norcassane-type diterpenes isolated Five new poly-O-acylated jatrophane diterpenes, including from CH2Cl2 extract of Caesalpinia crista L. (Caesalpinia- 1a,13b,14atrihydroxy-3b,7b-dibenzoyloxy-9b,15b-diace- ceae) from Myanmar and Indonesia were evaluated for their toxyjatropha-5,11 E-diene (196), 1a,8b,9b,14a,15b-penta- antimalarial activity against FCR-3/A2 clone. Caesalpinins acetoxy-3b-benzoyloxy-7-oxojatropha-5,12-diene (197), MA (149), ME–MJ (150–155), ML (156), norcaesalpinins 7,8b,9b,14a,15b-pentaacetoxy-3b-benzoyloxy-1a,5b-dihy- MC (157) and MD (158), caesalpinins C–F (159–162), J–K droxyjatropha-6(7),12-diene (198) and 1a,7,8b,9b,14a,15b- (163–164), N (165) and P (166), norcaesalpinins A–F (167– hexaacetoxy-3b-benzoyloxy-5b-hydroxyjatropha-6(7), 172), caesalmins B (173) and C (174), caesaldekarin E (175), 12-diene (199) were isolated from the white latex of 2-acetoxycaesaldekarin E (176), 2-acetoxy-3-deacetoxycae- Pedilanthus tithymaloides (L.) Poit. (Euphorbiaceae). These saldekarin E (177), 14(17)-dehydrocaesalmin F (178), highly oxygenated diterpenes possess a rare O-acetyl enol bonducellpins B (179) and C (180), 7-acetoxybonducellpin C moiety and showed antiplasmodial activity against K1 strain: (181) and 1-deacetoxy-1-oxocaesalmin C (182) displayed 196 (IC50 = 5.9 mM), 197 (IC50 = 4.9 mM), 198 (IC50 = [104] antimalarial activity with IC50 values of: 3.5, 3.6, 4.1, 2.5, 7.0, 6.0 mM) and 199 (IC50 = 5.8 mM). 2.1, 1.9, 0.65, 3.1, 1.0, 0.76, 0.8, 6.5, 0.65, 1.0, 0.40, 0.12, 1.7, Figure 10 shows diterpenes with moderate or promising 0.8, 0.26, 5.0, 2.0, 0.09, 0.14, 0.80, 3.4, 4.0, 6.5, 0.098, 0.2, activity in vitro against various strains of P. falciparum.

O O O O OH HO 129 O HO OH H H EZ O 132 HO O HO 130 131 HO OH O O OH H O H 133 O 134 H O OH O 137 O 135 O OH H O O H O R2 O O O H H O 145 O OR1 O H O O O HO O O 142 O 5 5 141 O O O 136.R1 H, R2 CH3 OCH O 5 5 3 O 138.R1 CH3,R2 CH3 H H O O O 5 5 O 139.R1 COPh, R2 H O O 140.R 5 COPh, R 5 CH 1 2 3 O H O O O H O O H 144 OH O O O O O O O O 146 OCH O 3 O O O OH O O O O O OH O O 143 H O O O HO O OH R 147 OH 1 H O O H O R2 H O R H 6 148 O H R R 3 OH 5 O R4 5 α β 5 5 5 5 5 R1 155. R1 -OAc, -H, R2 R3 R4 H, R5 OAc, R6 CH2 H R 5 α β 5 5 5 5 5 5 157. R1 -OAc, -H, R2 R3 H, R4 R5 OAc, R6 O 5 5 5 5 5 5 H R6 158. R1 R6 O, R2 R3 H, R4 R5 OAc 159. R 5 α -OAc, β -H, R 5 R 5 R 5 H, R 5 OAc, R 5 CH R R 1 2 4 5 3 6 2 2 4 5 5 5 5 5 5 α β OH 162. R1 O, R2 R3 R5 H, R4 OAc, R6 -H, -COOCH3 R 5 5 5 5 5 5 α β 3 163. R1 O, R2 R3 H, R4 R5 OAc, R6 -H, -COOCH3 166. R15 α -OAc, β -H, R 5 OAc, R 5 R 5 R 5 H, R 5 CH 149. R 5 R 5 OAc, R 5 R 5 R 5 H, R 5 CH 2 3 4 5 6 2 1 2 3 4 5 6 3 167. R15 α -OAc, β -H, R 5 OAc, R 5 R 5 R 5 H, R 5 O 5 5 5 5 5 5 2 3 4 5 6 151. R1 R2 OAc, R3 R4 R6 H, R5 COOCH3 5 α β 5 5 5 5 5 5 5 5 5 5 5 168. R1 -OAc, -H, R2 R4 R5 H, R3 OAc, R6 O 152. R1 R3 R4 OAc, R2 R6 H, R5 COOCH3 5 α β 5 5 5 5 5 5 5 5 5 5 5 170. R1 -OAc, -H, R2 R3 R4 H, R5 OH, R6 O 153. R1 R3 OAc, R2 R6 H, R4 OH, R5 COOH 5 5 5 5 5 5 171. R 5 α -OAc, β -H, R 5 R 5 R 5 H, R 5 OAc, R 5 O 154. R1 R2 R3 R5 H, R4 OH, R6 CH3 1 2 4 5 3 6 5 5 5 5 5 5 172. R 5 R 5 O, R 5 R 5 H, R 5 OAc, R 5 OH 161. R1 R3 OAc, R2 R4 R6 H, R5 COOCH3 1 6 2 3 4 5 5 5 5 5 5 5 174. R 5 α -OAc, β -H, R 5 R 5 H, R 5 R 5 OAc, R 5 CH 164. R1 OAc, R2 R3 R5 H, R4 OH, R6 CH3 1 2 3 4 5 6 2 5 5 5 5 5 5 5 α β 5 5 5 5 5 165. R1 OAc, R2 R3 R6 H, R4 OH, R5 CHO 178. R1 -OAc, -H, R2 R3 OAc, R4 R5 H, R6 CH2 5 5 5 5 5 5 5 5 5 5 5 5 α β 180. R1 OAc, R2 R3 R6 H, R4 OH, R5 COOCH3 179. R1 O, R2 R3 H, R4 OAc, R5 OH, R6 -H, -COOCH3 5 5 5 5 5 5 5 5 5 5 5 5 181. R1 R4 OAc, R2 R3 R6 H, R5 COOCH3 182. R1 O, R2 R3 H, R4 R5 OAc, R6 CH2

Figure 10 Diterpenes with moderate or promising activity in vitro against various strains of P. falciparum Author Copy: This article was published by the Pharmaceutical Press, which has granted the author permission to distribute this material for personal or professional (non-commercial) use only, subject to the terms and conditions of the Pharmaceutical Press Licence to Publish. Any substantial or systematic reproduction, re-distribution, re-selling, sub-licensing or modification of the whole or part of the article in any form is expressly forbidden. 1416 Journal of Pharmacy and Pharmacology 2009; 61: 1401–1433

150 H 156 H O H O H O AcO H HO OH H OAc OH O OAc 169 R O 1 O OAc H OH AcO R R1 H 2 H OH O R O H 3 H O 5 5 5 O OH 175. R1 R3 H, R2 OAc OH 183 5 5 5 OH 176. R1 R2 OAc, R3 H O 5 5 5 OAc 177. R1 OAc, R2 R3 H R2 OAc 160. R 5 α -OAc, β -H, R 5 OAc H O 1 2 O H 188 5 α β 5 187 173. R1 -OAc, -H, R2 H O O H O H O H H OH OH H O OAc H H 185 H O 186 OAc OH OAc H CH2OH H OH OAc O OH 189 O OH OAc 184 O 190 OH HO HO O O O HO O H O 191 HO OH O 192 O HO HO O 193 O O O HO O OH O

OH OH HO HO HO AcO

O OAc O H 194 H H O 195 O

196 AcO AcO RO AcO AcO AcO

O OAc O OAc O H O H HO OAc OAc OAc O 198.R5 H 197 199. R 5 Ac

Figure 10 (Continued)

Triterpenes (3R,22R)(200) displayed an IC50 of 18 mM and 7 mM on From the stem bark of Ekebergia capensis Sparrm. (Melia- FCR-3 and K1, respectively, and showed in vivo parasitaemia [105] ceae), a triterpenoid derivative was isolated and screened suppression of 52.9% when given intraperitoneally. against FCR-3 and K1 strains. 2,3,22,23-Tetrahydroxy- Seven new and two known compounds were isolated from 2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene an ethyl acetate extract of the leaves of Nuxia sphaerocephala

Baker (Buddlejaceae) and have been considered moderately moderate activity with an IC50 of 9.7 mM on D6 and 12.7 mM active, 3-oxolupenal (201) and 3b-hydroxy-lupenal (202) on W2.[112] Three triterpenes were isolated from Cogniauxia having the best activity with IC50 values of 3.6 and 7.2 mM, podolaena Baill. (Cucurbitaceae), cucurbitacin B (216), respectively, against FcB1.[106] One new and eight known cucurbitacin D (217) and 20-epibryonolic acid (218). All ceanothane- and lupane-type triterpenes were isolated from compounds obtained were assayed for antiplasmodial activity the root bark of Ziziphus cambodianus Pierre (Rhamnaceae). (on FcM29) and cytotoxicity. The IC50 values were 2.9, The new compound, 3-O-vanillylceanothic acid (203), and 7.8 and 3.7 mM, respectively. Both 216 and 217 have high two known compounds, 2-O-E-p-coumaroyl alphitolic acid cytotoxicity, whereas 218 showed a better selectivity (204) and zizyberenalic acid (205), exhibited notable index.[113] A compound was isolated from the active fraction antiplasmodial activity with IC50 values of 5.8, 1.5 and of Salvia radula Epling (Lamiaceae) and identified as [107] 6.6 mM, respectively. betulafolientriol oxide (219). It displayed moderate anti- [114] Bioassay-directed fractionation led to the isolation of malarial activity (IC50 = 10.4 mM). betulinic acid 3-caffeate (206) from a sample of the dried A quassinoid, neosergeolide (220), isolated from the roots leaves, twigs, and branches of Diospyros quaesita Thwaites and stems of Picrolemma sprucei Hook.f. (Simaroubaceae), (Ebenaceae). This compound showed strong antimalarial possessed a significant inhibitory effect (more active than [49] activity against D6 and W2 with IC50 values of 1.40 and quinine and chloroquine) on K1 strain (IC50 = 2 nM). Two 0.98 mM, respectively. Evaluation of 206 in the human oral new limonoids, domesticulide B (221) and C (222), and three epidermoid (KB) cancer cell line revealed cytotoxicity at an more known ones, methyl 6-acetoxyangolensate (223), [108] IC50 of 4.0 mM. Phytochemical investigation of the azadiradione (224) and dukunolide C (225), were isolated CH2Cl2 extracts of Erythrina stricta Roxb. (Leguminosae) from seeds of Lansium domesticum Correˆa (Meliaceae) and roots and Erythrina subumbrans Merr. (Leguminosae) stems showed antimalarial activity against K1 with IC50 values of [115] led to the isolation of one triterpene, soyasapogenol B (207), 6.0, 4.1, 7.2, 6.4, 9.6 mM, respectively. Marked antimalar- which exhibited moderate antiplasmodial activity (10.0 mM) ial activity was observed for anthothecol (226), a limonoid of against K1.[18] Friedelan-3-one (208) was isolated from the Khaya anthotheca C.DC. (Meliaceae). IC50 values were 1.4 [116] root bark of Harungana madagascariensis Poir. (Clusia- and 0.17 mM against W2 strain using two different assays. ceae). Its antiplasmodial activity was evaluated against W2 In the search for active principles from the stem bark of [73] strain and gave an IC50 of 7.7 mM. Garcinane (209) was Entandrophragma angolense C.DC. (Meliaceae), 7a-obacu- isolated from the roots of Garcinia polyantha Oliv. nyl acetate (227) was isolated and tested against W2 strain. It [117] (Clusiaceae) and exhibited antimalarial activity against exhibited antimalarial activity with an IC50 of 4.0 mM. [35] NF54 with IC50 ranging from 2.5 to 4.1 mM. A new Two limonoids isolated from the seeds of Chisocheton bisnortriterpene quinone methide, 20-epi-isoiguesterinol siamensis Craib (Meliaceae) were tested for antimalarial (211) and a known compound, isoiguesterin (210), were activity. Dysobinin (228) and mahonin (229) showed an isolated from the petroleum ether extract of the roots of inhibitory effect against K1 with IC50 values of 4.2 and [118] Salacia madagascariensis DC. (Celastraceae). Compound 5.7 mM, respectively. The dicholoromethane extract of 211 was active with IC50 of 0.16 mM on D6 and W2, and Pseudocedrela kotschyi Harms (Meliaceae) root commonly 210 with IC50 of 0.50 and 0.42 mM on D6 and W2, used in Malian traditional medicine led to the isolation of two respectively.[109] known compounds, 7-deacetylgedunin (230) and 7-deacetyl- Bioassay-directed fractionation led to the isolation of 7-oxogedunin (231), which exhibited activity against K1 [119] 2a,3b-dihydroxyolean-12-en-28-oic acid (212) from a sam- (IC50 = 3.1 and 4.1 mM, respectively). Compound 231 ple of Grewia bilamellata Gagnep. (Tiliaceae), which was also isolated from the stem bark of Ekebergia capensis displayed antimalarial activity against D6 and W2 (21.1 Sparrm. (Meliaceae) and screened against FCR-3 strain with [41] [105] and 8.6 mM) without significant cytotoxicity. A bioassay- an IC50 of 6 mM. guided fractionation from Morinda lucida Benth. (Rubia- Figure 11 shows triterpenes with moderate or promising ceae) leaves and from Satureja parvifolia (Phil.) Epling activity in vitro against various strains of P. falciparum. (Lamiaceae) resulted in the isolation of two known triterpenic acids, ursolic acid (213) and oleanolic acid. Steroids These two compounds had already been evaluated in vitro Four new pregnane glycosides, 12-O-benzoyl-20-O-acetyl but in these two studies some activity was observed for the 3b,12b,14b,20b-tetrahydroxy-(20S)-pregn-5-ene-6-deoxy- first time, with IC50 of 32.3 and 19.8 mM for oleanolic acid, 3-O-methyl-b-D-allopyranosyl(1!4)-b-D-cymaropyranosyl and 6.8 and 10.7 mM for ursolic acid. In vivo, oleanolic acid (1!4)-b-D-cymaropyranoside (232), 12-O-benzoyl-20-O- at a daily dose of 200 mg/kg produced 37.4% chemosup- acetyl 3b,7a,12b,14b,20b-tetrahydroxy-(20S)-pregn-5-ene- [58,110] pression. Bioactivity-guided fractionation of the pet- 6-deoxy-3-O-methyl-b-D-allopyranosyl-(1!4)-b-D-cymaro- roleum ether extracts of the whole plants of Viola verecunda pyranosyl-(1!4)-b-D-cymaropyranoside (233), 12-O-ben- A. Gray (Violaceae) led to the isolation of epi-oleanolic acid zoyl-20-O-acetyl 3b,5a,12b,14b,20b-pentahydroxy-(20S)- (214), a triterpenoid, displaying high antiplasmodial activity pregn-6-ene-b-D-glucopyranosyl-(1!4)-6-deoxy-3-O- [111] against FcB1 strain (IC50 = 39 nM). methyl-b-D-allopyranosyl-(1!4)-b-D-cymaropyranosyl- Bioassay-guided fractionation of the antimalarial-active (1!4)-b-D-cymaropyranoside (234) and 12,20-dibenzoyl- CHCl3 extract of the dried stem of Nauclea orientalis (L.) L. 3b,12b,14b,20b-tetrahydroxy-(20S)-pregn-5-ene-b-D-gluco- (Rubiaceae) resulted in the isolation of a known compound, pyranosyl-(1!4)-6-deoxy-3-O-methyl-b-D-allopyranosyl- 3a,23-dihydroxyurs-12-en-28-oic acid (215), which showed (1!4)-b-D-cymaropyranosyl-(1!4)-b-D-cymaropyranoside

(235) were isolated from Caralluma tuberculata N.E.Br. Figure 12 shows steroids with moderate or promising (Asclepiadaceae), in addition to a known one, russelioside E activity in vitro against various strains of P. falciparum. (236). All the isolated compounds were tested for their Table 3 gives the tested terpenoid compounds presenting antimalarial activity against K1 and had IC50 = 7.4, 6.5, 9.6, low or no activity in vitro against various strains of [120] [41,58,65,74,78,80,87,89,92,94,105,110,115,117–119,121–140] 5.7 and 7.5 mM, respectively. P. falciparum.

5 5 5 OH 201.R1 R2 O, R3 CHO HO 5 5 5 R 202.R1 OH, R2 H, R3 CHO 3 H HO OH OH 200 H

H 205 R2 R HOOC O 1 H HO COOH COOH O O H O H H 206 203 OH H COOH O H HO 207 O HO H HO HO HO

H OH HO O H H H COOH 204 O O H H 209 O O HO 208 H OH

COOH HO O H COOH O HO 212 HO 213 HO 211 HO 210 OH O H O H COOH COOH H OH O HO H H O 215 214 HO 216 HO O H OH

OH O O OH OH O H H OH HO OH O OH OH O H CO CH H HO 2 3 O O O OCOCH 217 3 O H O O 218 HO 219 220

Figure 11 Triterpenes with moderate or promising activity in vitro against various strains of P. falciparum

O HO O O O 221 222 223 O O 224 O O O O O OH O O O O OAc H O OAc OAc H O O OCH3 H O OAc O OCH H 3 O OCH3 O O O 225 O O 228 226 227 O O O O OH O O O AcO O O OH O O O O O O OAc O OH O O O O O O O 230 229 231

O O O O O O O O O O O O OH O O

Figure 11 (Continued)

OR 2 OR3 OR1 OR2

OH Sugar OH Sugar O R1 O 5 5 5 5 232. R1 H, R2 Benzoyl, R3 Acetyl, Sugar I 233. R 5 OH, R 5 Benzoyl, R 5 Acetyl, Sugar 5 I 1 2 3 5 5 5 5 5 5 5 234. R1 Benzoyl, R2 Acetyl, Sugar II 235. R1 H, R2 R3 Benzoyl, Sugar II 5 5 5 5 236. R1 H, R2 Benzoyl, R3 Acetyl, Sugar II

O 5 I O O 5 II O O OH O O O O HO O O O OCH3 OCH3 OH OCH HO OCH OCH 3 OH 3 3 H3CO OH OH

Figure 12 Steroids with moderate or promising activity in vitro against various strains of P. falciparum Alkaloids from the alkaloidal fraction, budmunchiamine K (237), 6- hydroxybudmunchiamine K (238), 5-normethylbudmunchi- Ornithine and lysine derivatives amine K (239), 6-hydroxy-5-normethylbudmunchiamine K The methanolic extract of Albizia gummifera C.A.Sm. (Legumi- (240) and 9-normethylbudmunchiamine K (241). These alkaloids nosae) was fractionated to isolate five known spermine alkaloids exhibited good activity with IC50 values of 0.18, 0.29, 0.20, 0.33

Table 3 Terpenoid compounds presenting low or no activity in vitro against various strains of P. falciparum

Compound Plant Family IC50 (mM) Reference no.

16-Hydroxycleroda-3,13(14)Z-dien-15,16-olide Goniothalamus marcanii Craib Annonaceae 11.3 (K1) 74 Lupeol Holarrhena floribunda T.Durand & Schinz Apocynaceae >50 (FCR-3/3D7) 121 3-O-(30-Hydroxyeicosanoyl)lupeol Holarrhena floribunda T.Durand & Schinz Apocynaceae >50 (FCR-3/3D7) 121 3-O-[(20-(Tetracosyloxy)acetyl]lupeol Holarrhena floribunda T.Durand & Schinz Apocynaceae >50 (FCR-3/3D7) 121 3-O-[(100-Hydroxyoctadecyloxy)-20- Holarrhena floribunda T.Durand & Schinz Apocynaceae >50 (FCR-3/3D7) 121 hydroxypropanoyl]lupeol Uzarigenin Calotropis gigantean (L.) W.T.Aiton Asclepiadaceae >50 (K1) 122 Calactin Calotropis gigantean (L.) W.T.Aiton Asclepiadaceae >50 (K1) 122 Calotropin Calotropis gigantean (L.) W.T.Aiton Asclepiadaceae >50 (K1) 122 Taraxasteryl acetate Calotropis gigantean (L.) W.T.Aiton Asclepiadaceae >50 (K1) 122 Esacetyl-a-cyclopyrethrosin Oncosiphon piluliferum (L.f.) Ka¨llersjo¨ Asteraceae 16.7 (D10) 78 1,10-Dioxo-1,10-deoxy-1,10-secogorgonolide Artemisia gorgonum Webb Asteraceae 50.0 (FcB1) 80 3b,4b-Epoxy-1b,10b-epiarborescin Artemisia gorgonum Webb Asteraceae 50.4 (FcB1) 80 Arborescin Artemisia gorgonum Webb Asteraceae 15.3 (FcB1) 80 1b,10b-Epoxy-2a-hydroxykauniolide Artemisia gorgonum Webb Asteraceae 22.1 (FcB1) 80 1a,4a,10a-Trihydroxy-5a,11bH-guaia- Artemisia gorgonum Webb Asteraceae 32.1 (FcB1) 80 2-en-12,6a-olide Ridentin Artemisia gorgonum Webb Asteraceae 21.4 (FcB1) 80 Anthecularin Anthemis auriculata Boiss. Asteraceae >50 (K1) 123 Anthecotulide Anthemis auriculata Boiss. Asteraceae 16.1 (K1) 87 4-Acetoxyanthecotulide Anthemis auriculata Boiss. Asteraceae 16.7 (K1) 87 Methyl populnoate Austroplenckia populnea (Reissek) Lundell Celastraceae >50 (D6) 124 Populnoic acid Austroplenckia populnea (Reissek) Lundell Celastraceae >50 (D6) 124 Stigmast-5-en-3-O-b-(D-glucopyranoside) Austroplenckia populnea (Reissek) Lundell Celastraceae >50 (D6) 124 Endodesmiadiol Endodesmia calophylloides Benth. Clusiaceae 13.0 (W2) 125 Canophyllal Endodesmia calophylloides Benth. Clusiaceae 18.2 (W2) 125 Cerin Endodesmia calophylloides Benth. Clusiaceae 14.1 (W2) 125 Morelloflavone Endodesmia calophylloides Benth. Clusiaceae 23.6 (W2) 125 3b-Acetoxyoleanolic acid Endodesmia calophylloides Benth. Clusiaceae 13.1 (W2) 125 Sutherlandioside A Sutherlandia frutescens (L.) R. Br. Fabaceae >50 (D6/W2) 126 Sutherlandioside B Sutherlandia frutescens (L.) R. Br. Fabaceae >50 (D6/W2) 126 Sutherlandioside C Sutherlandia frutescens (L.) R. Br. Fabaceae >50 (D6/W2) 126 Sutherlandioside D Sutherlandia frutescens (L.) R. Br. Fabaceae >50 (D6/W2) 126 Laetianolide A Laetia procera (Poepp.) Eichler Flacourtiaceae 57.6 (F32) 92 27.5 (FCb1) 15-O-Ethylleopersin C Leonurus cardiaca L. Lamiaceae >50 (D6/W2) 127 15-O-Methylleopersin C Leonurus cardiaca L. Lamiaceae >50 (D6/W2) 127 15-Epi-O-methylleopersin C Leonurus cardiaca L. Lamiaceae >50 (D6/W2) 127 12,17-Diacetoxy,15-hydroxy,2-oxo,3,13 Gomphostemma crinitum Wall. Lamiaceae 22.14 (MRC-02) 128 E(14)-diene clerodane Fagraldehyde Fagraea fragrans Roxb. Loganiaceae >50 (W2) 129 Geranylfarnesol Thalia geniculata L. Marantaceae 12.7 130 Kurubasch aldehyde Trichilia emetica Vahl. Meliaceae 76 (3D7) 131 16-Oxolabda-8(17),12(E)-dien-15-oic acid Turraeanthus africana Pellegr. Meliaceae 83.1 (F32) 132 Methyl 14,15-epoxylabda-8(17),12E- Turraeanthus africana Pellegr. Meliaceae >50 (F32) 133 diene-16-oate Ekeberin D4 Ekebergia capensis Sparrm. Meliaceae 40 (FCR-3) 105 Domesticulide D Lansium domesticum Correˆa Meliaceae 11.8 (K1) 115 6-Acetoxymexicanolide Lansium domesticum Correˆa Meliaceae 18.4 (K1) 115 Walsuronoid Walsura robusta Roxb. Meliaceae 40% at 40 mM 134 (3D7) Walsuronoid B Walsura robusta Roxb. Meliaceae 40% at 40 mM 134 (3D7) 24-Methylene cycloartenol Entandrophragma angolense C.DC. Meliaceae 12.3 (W2) 117 7a-Acetoxydihydronomilin Entandrophragma angolense C.DC. Meliaceae 34.9 (W2) 117 Methylangolensate Entandrophragma angolense C.DC. Meliaceae 48.7 (W2) 117 6a-Acetoxyepoxyazadiradione Chisocheton siamensis Craib Meliaceae 12.0 (K1) 118 Kotschyin A Pseudocedrela kotschyi Harms Meliaceae > 5 (K1) 119 Methyl 3,4-dihydroxy-5-(3-methyl-2- Piper glabratum Kunth Piperaceae 17.4 (F32) 135 butenyl)benzoate Methyl 4-hydroxy-3-(3-methyl-2- Piper glabratum Kunth Piperaceae 12.7 (F32) 135 butenyl)benzoate (Continued) Author Copy: This article was published by the Pharmaceutical Press, which has granted the author permission to distribute this material for personal or professional (non-commercial) use only, subject to the terms and conditions of the Pharmaceutical Press Licence to Publish. Any substantial or systematic reproduction, re-distribution, re-selling, sub-licensing or modification of the whole or part of the article in any form is expressly forbidden. Antimalarial plant compounds Joanne Bero et al. 1421

Table 3 (Continued)

Compound Plant Family IC50 (mM) Reference no.

Benzoic acid,3-[2-(acetyloxy)-3-methyl- Piper glabratum Kunth Piperaceae 34.0 (F32) 135 3-buten-1-yl]-4,5-dihydroxy-,methyl ester 3-(Z)-Caffeoyllupeol Bruguiera parviflora Wight Rhizophoraceae 14.6 (K1) 136 Oleanolic acid Morinda lucida Benth. Rubiaceae 32.3 (CQs) 110 Satureja parvifolia (Phil.) Epling Lamiaceae 19.8 (3D7) 58 b-Acetylolean-12-en-28-olic acid Prismatomeris fragrans Geddes Rubiaceae 11.9 (K1) 137 Methyl uguenenoate Vepris uguenensis Engl. Rutaceae 20.7 (3D7) 65 27.5 (FCM29) 3,4-Dihydro-methylcatalpol Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 Scrolepidoside Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 Catalpol Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 6-O-Methylcatalpol Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 Sinuatol Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 aucubin Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 6-O-b-D-Xylopyranosylaucubin Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 Ajugol Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 Ajugoside Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 Iridoid-related aglycone Scrophularia lepidota Boiss. Scrophulariaceae >50 (K1) 138 3-O-b-D-glucopyranosylpseudojujubogenin Bacopa monniera Wettst Scrophulariaceae >50 139 Bacoside A3 Bacopa monniera Wettst Scrophulariaceae >50 139 Bacoside A6 Bacopa monniera Wettst Scrophulariaceae >50 139 Bacopaside II Bacopa monniera Wettst Scrophulariaceae >50 139 Bacopaside IV Bacopa monniera Wettst Scrophulariaceae >50 139 Bacopaside V Bacopa monniera Wettst Scrophulariaceae >50 139 Bacopaside X Bacopa monniera Wettst Scrophulariaceae >50 139 Bacopaside N2 Bacopa monniera Wettst Scrophulariaceae >50 139 Bacopasaponin C Bacopa monniera Wettst Scrophulariaceae >50 139 Bacopasaponin G Bacopa monniera Wettst Scrophulariaceae >50 139 Buddlejasaponin Scrophularia cryptophilla Boiss. & Heldr. Scrophulariaceae 24.5 (K1) 140 3a,20-Lupandiol Grewia bilamellata Gagnep. Tiliaceae 19.8 (D6) 41 19.1 (W2) Aulacocarpin A Aframomum zambesiacum K. Schum Zingiberaceae 13.7 (FcB1) 89 Zambesiacolactone A Aframomum zambesiacum K. Schum Zingiberaceae 17.2 (FcB1) 89 Zambesiacolactone B Aframomum zambesiacum K. Schum Zingiberaceae 15.5 (FcB1) 89 (1R,2S,5S,9S,10S,11R,13R)-1,2,11- Kaempferia marginata Carey Zingiberaceae 27.5 (K1) 94 trihydroxypimara-8(14),15-diene

and 0.24 mM, respectively, on NF54, and 1.43, 1.73, 1.88, 1.72 siamea Lam. (Leguminosae). It showed promising antiplas- [144] and 1.79, respectively, on ENT30. Four of these alkaloids were modial activity (IC50 23.5 nM). Zanthoxylum rhoifolium further evaluated intraperitoneally for activity against P. berghei Lam. (Rutaceae) bark is a medicinal plant traditionally used in vivo. The alkaloids showed chemosuppression percentages of in French Guiana to treat and prevent malaria. Bioassay- parasitaemia in mice ranging from 43 to 72% at 20 mg/kg per day guided fractionation of the alkaloid extract yielded three TheuseoftheextractsofA. gummifera for the treatment of benzophenanthridine alkaloids. Dihydronitidine (246) was [145] malaria in traditional medicine seems to have a scientific evaluated against FcB1 (IC50 = 4.9 mM). Biologically basis.[141] Vertine (242) and epi-lyfoline (243) were isolated guided fractionation of the methanolic extract of the roots of from Heimia salicifolia Link & Otto (Lythraceae) and showed Zanthoxylum flavum Vahl (Rutaceae) led to the isolation of antimalarial activity with IC50 values of 10.9 and 6.7 mM, two alkaloids, dihydrochelerythrin (247) and chelerythrine respectively.[142] A new lycorine derivative LT1 (244), 1-O- acetonate (248). Compound 247 was only moderately active (30S)-hydroxybutanoyllycorine was isolated from the aerial part with an IC50 of 10.6 mM on D6. Compound 248 displayed and bulbs of Lycoris traubii Hayward (Amaryllidaceae). It greater activity with IC50 values of 5.7 and 3.4 mM on D6 showed significant activity against FCR-3 and K1 strains and W2 strains, respectively.[40] Decoction of Strychnopsis [143] (IC50 = 1.2 and 1.6 mM, respectively). thouarsii Baill. (Menispermaceae) is used in Malagasy Figure 13 shows alkaloids derived from ornithine and traditional medicine to fight malaria. It has been shown lysine with moderate or promising activity in vitro against that this traditional remedy prevents malaria infection by various strains of P. falciparum. targeting Plasmodium at its early liver stage. Bioassay- guided fractionation of S. thouarsii stem barks extracts, Phenylalanine and tyrosine derivatives using a rodent Plasmodium yoelii liver stage parasites A novel alkaloid with an unprecedented tricyclic skeleton, inhibition assay, led to the isolation the new morphinan cassiarin A (245), was isolated from the leaves of Cassia alkaloid tazopsine (249) together with sinococuline (250). Author Copy: This article was published by the Pharmaceutical Press, which has granted the author permission to distribute this material for personal or professional (non-commercial) use only, subject to the terms and conditions of the Pharmaceutical Press Licence to Publish. Any substantial or systematic reproduction, re-distribution, re-selling, sub-licensing or modification of the whole or part of the article in any form is expressly forbidden. 1422 Journal of Pharmacy and Pharmacology 2009; 61: 1401–1433

O O R3 R2

N N H O H O HO HO N N R O 1 H N N H H H H 5 5 5 237. R1 H, R2 CH3, R3 CH3 5 5 5 244 O O 238. R1 OH, R2 CH3, R3 CH3 OH O 5 5 5 OH O OH 239. R1 H, R2 H, R3 CH3 242 243 5 5 5 240. R1 OH, R2 H, R3 CH3 O 5 5 5 241. R1 H, R2 CH3, R3 H H O H O N

Figure 13 Alkaloids derived from ornithine and lysine with moderate or promising activity in vitro against various strains of P. falciparum

Compounds 249 and 250 exhibited selective inhibitory and 1,2-dehydrotelobine (266). They demonstrated antiplas- activity (SI > 13.8) against P. yoelii liver stage in vitro. modial activity with IC50 values of 1.72, 0.93, 1.39 and Tazopsine showed the most potent inhibitory activity with an 12.4 mM, respectively, on 3D7, and 0.35, 1.10, 1.63 and [154] IC50 value of 3.1 mM. Sinococuline was both slightly less 1.52 mM, respectively, on W2. Three new fully dehy- [146,147] 0 active (IC50 = 4.5 mM) and less toxic. Dehydroroe- drogenated naphthylisoquinoline alkaloids, the 7,1 -coupled merine (251) was isolated from Stephania rotunda Lour. ent-dioncophylleine A (267), the 7,10-coupled 50-O- (Menispermaceae) and was found to be the most active demethyl-ent-dioncophylleine A (268), and the 7,80-linked [148] against W2 with an IC50 value of 0.36 mM. Two new dioncophylleine D (269), were isolated from the leaves of the alkaloids, desmorostratine (252) and discretine N-oxide liana Ancistrocladus benomensis Rischer & G.Bringmann (253), were isolated from the stem bark of Desmos rostrata (Ancistrocladaceae). Compounds 267 and 268 exhibited (Merr. & Chun) P.T.Li (Annonaceae), together with five moderate antiplasmodial activity against K1 with IC50 known alkaloids including discretine (254) and dehydrodis- values of 10.5 and 8.6 mM, respectively. Compound 269 [155] cretine (255). Compounds 253, 254 and 255 inhibited FcB1 showed better activity with a low IC50 (1.3 mM). From the with IC50 values of 4.2, 1.6 and 0.9 mM, respectively, and roots of a recently discovered Ancistrocladus taxon with close showed weak cytotoxic activity. On the other hand, 252 had affinity to Ancistrocladus congolensis J. Le´onard (Ancistro- 0 an IC50 of 3.6 mM but was also moderately toxic (IC50 = cladaceae), six new naphthylisoquinoline alkaloids, 5 -O- [149] 0 2.4 mM). A new dimeric aporphine alkaloid, bidebiline E demethylhamatine (270), 5 -O-demethylhamatinine (271), 0 (256), was isolated from the roots of Polyalthia cerasoides 6-O-demethylancistroealaine A (272), 6,5 -O,O-didemethylan- (Roxb.) Bedd. (Annonaceae). It exhibited antimalarial cistroealaine A (273), 5-epi-6-O-methylancistrobertsonine A [150] 0 activity against K1 (IC50 = 7.7 mM). Three alkaloids, (274), and 5-epi-4 -O-demethylancistrobertsonine C (275), melosmine (257), atherospermidine (258) and isomoschato- and also the known 6-O-demethylancistrobrevine A (276), line (259), isolated from the ethyl acetate extract of the stem were isolated. All of the naphthylisoquinoline alkaloids tested of Rollinia pittieri Saff. and Pseudomalmea boyacana (J.F. were found to exhibit antiplasmodial activity against K1 strain: [156] Macbr.) Chatrou (Annonaceae) exhibited moderate activity IC50 = 2.5, 7.2, 4.4, 5.4, 4.4, 6.2 and 5.0 mM, respectively. with IC50 values of 12.2, 10.6 and 10.9 mM, respectively, Figure 14 shows alkaloids derived from phenylalanine [151] against F32, and 10.4, 12.8 and 27.8 mM against W2. and tyrosine with moderate or promising activity in vitro Two bioactive bisbenzylisoquinolines, magnoline (260) and against various strains of P. falciparum. magnolamine (261), were isolated from the leaves of Michelia figo (Lour.) Sprenge (Magnioliaceae). Magnolamine showed Tryptophane derivatives mM mM a significant IC50 of 1.28 on K1 and less than 0.16 on Bioassay-guided fractionation of the antimalarial CHCl3 FCR3. Magnoline also inhibited both strains with an IC50 of extract of the dried stem of Nauclea orientalis (L.) L. [152] 1.51 mM on FCR3 and less than 0.16 mM on K1. A new (Rubiaceae) resulted in the isolation of a novel tetrahydro-b- diastereoisomer of the bis-benzylisoquinoline alkaloid rodia- carboline monoterpene alkaloid glucoside, naucleaorine 0 262 sine, 1S,1 R-rodiasine ( ), was isolated from Pseudoxandra (277), which showed activity with an IC50 of 6.9 mM on cuspidata Maas (Annonaceae) bark, used in French Guiana as D6 and 8.0 on W2.[112] An indole alkaloid, naucleofficine A an antimalarial. The antimalarial activity of this bark was (278), was isolated from the stems (with bark) of Nauclea mostly due to 262 (IC50 = 1.14 mM), which also displayed officinalis Pierre ex Pitard (Rubiaceae). Compound 278 low cytotoxicity.[153] The antiplasmodial activity of Triclisia exhibited moderate antimalarial activity against FCC1-HN sacleuxii Diels (Menispermaceae) was investigated on 3D7 with an IC50 value of 9.7 mM and no cytotoxic effect was and W2 strains. Phytochemical analysis of the root tertiary observed.[157] A dimeric indoloquinoline alkaloid, biscrypto- alkaloids fraction yielded four major compounds, phaeanthine lepine (279), originally obtained from the plant Cryptolepis (263), N-methylapateline (264), 1,2-dehydroapateline (265) sanguinolenta (Lindl.) Schltr. (Asclepiadaceae), showed

O O O HO O O H3CO O N N N O N O 248 H3CO 247 O 245 O O 246 OH O OCH 3 HO H CO N O 3 O H R1 H N NH H CO HO R2 O 3 253 NH O H O OCH3 HO OCH3 OCH3 251 252 OCH3 OH OCH3 5 5 249. R1 OH, R2 H 250. R 5 R 5 H OCH 1 2 HO O 3 H3CO NH OCH HO N O 3 H CO H 3 N N HO H CO 3 255 OCH 254 3 O OCH3 HN OCH3 257 OCH3 OH 256 O OCH3 OCH3 OCH3 OCH3 O H CO N 3 H CO N 3 O N OH H N OH HO H N H HO H 258 O O O 260 OH 261 OCH3 OH OH OCH3 H3CO OCH3 H3CO H3CO N N N N N OCH3 H OCH3 H3CO H O O O O 259 263 OCH3 HO OCH3 262 H CO 3 H3CO O O H3CO N N N N O N N O O O O O OH OH 264 265 O OCH3 266

OH OCH N N 3 H3CO HO N H CO OH OH 3 H3CO OH H3CO 267 268 H3CO HO 269 270 H3C NH OH OCH3 O OR1 H3C 5 O OCH OCH 272. R1 CH 3 3 273. R 5 H 1 OHOCH3 274 HO HO 275 H CO N N 3 H CO 271 N 3 OCH3 OCH3 N OCH3 OCH HO 3 276 N

OCH3 H3CO H3CO

Figure 14 Alkaloids derived from phenylalanine and tyrosine with moderate or promising activity in vitro against various strains of P. falciparum

[160] good antiplasmodial activity against K1 (IC50 of 0.27 mM), and 2.4, respectively, against W2 strain. Bioassay-guided [158] while the cytotoxicity (L6 cells) was 13.62 mM. Bio- fractionation of the EtOH extract of the stem bark of Funtumia logically guided fractionation of the methanolic extract of elastica Stapf (Apocynaceae) resulted in the isolation of four the roots of Zanthoxylum flavum Vahl (Rutaceae) led to the steroidal alkaloids, holarrhetine (286), conessine (287), isolation of dihydrorutaecarpine (280) which displayed higher holarrhesine (288) and isoconessimine (289). They exhibited activity with IC50 values of 5.7 and 3.4 mM on D6 and W2 antiplasmodial activity against FcB1 strain with IC50 values of [40] strains, respectively. Isosungucine is a quasi-symmetric 1.13, 1.04, 0.97 and 3.39 mM and weak cytotoxicity (L-6 cell [161] bisindolomonoterpenoid alkaloid isolated from the roots of line) with IC50 values of 5.13, 14.6, 7.49 and 36.55 mM. Strychnos icaja Baill. (Loganiaceae). The antimalarial Figure 16 shows steroidal alkaloids with moderate activity against the P. vinckei petteri murine strain was or promising activity in vitro against various strains of determined in vivo. In the Peters 4-day suppressive test, the P. falciparum. compound suppressed parasitaemia by almost 50% on day 4 at a dose of 30 mg/kg given intraperitoneally.[159] Other N-containing compounds Figure 15 shows alkaloids derived from tryptophane with Bioassay-guided fractionation of the EtOAc extract of the moderate or promising activity in vitro against various strains roots of Thai Ziziphus oenoplia L. Mill. var. brunoniana of P. falciparum. (Rhamnaceae) resulted in the isolation of two new 13- membered cyclopeptide alkaloids of the 5(13) type, ziziphine Steroidal alkaloids N(290) and Q (291), which exhibited notable antiplasmodial [162] Bioguided phytochemical investigation of Sarcococca hoo- activity with IC50 values of 6.4 and 5.9 mM, respectively. keriana Baill. (Buxaceae) yielded two new pregnane-type Three alkamides were isolated from the leaves of Zanthox- steroidal alkaloids hookerianamide H (281) and hookeriana- ylum syncarpum Tul. (Rutaceae). Compound 292,the mide I (282), along with three known alkaloids, Na- racemic form of the known compound syncarpamide, methylepipachysamine D (283), sarcovagine C (284) and showed moderate antiplasmodial activity, with IC50 values dictyophlebine (285). These compounds showed reasonable of 4.2 and 6.1 mM against D6 and W2 clones, respectively. [163] antiplasmodial activity with IC50 values of 3.5, 6.6, 10.3, 3.4 Cytotoxicity was evaluated at an IC50 of 10.3 mM.

O N 280 N O N N O N N N H 279 H H OH N N H OCH NH 277 3 OH O O N OH H OH O O O OH HO OH 278 HO OH

Figure 15 Alkaloids derived from tryptophane with moderate or promising activity in vitro against various strains of P. falciparum

R1 N 5 N 282. R1 H N 5 283. R1 CH3 H H O H O Tig 5 H H O H H H H R N 1 N H H 281 N H H 5 5 O H R 284. R1 Tig, R2 OAc 2 5 5 285. R1 CH3, R2 H

O H H N N O H H H H H H H H N N R1 R1 5 5 286. R1 CH3 287. R1 CH3 5 5 288. R1 H 289. R1 H

Figure 16 Steroidal alkaloids with moderate or promising activity in vitro against various strains of P. falciparum

OR1 H O H O H N H HN H R3 N N O HN O O H O O H3CO H OCH3 292 N

5 5 5 290. R1 R2 CH3, R3 CH2CH(CH3)2 5 5 291. R1 R2 CH3, R3 = CH(CH3)2

Figure 17 Other N-containing compounds with moderate or promising activity in vitro against various strains of P. falciparum

Table 4 Alkaloids presenting low or no activity in vitro against various strains of P. falciparum

Compound Plant Family IC50 (mM) Reference no.

Predicentrine Desmos rostrata (Merr. & Chun) P.T.Li Annonaceae 27.8 (FcB1) 149 Aristolactam Desmos rostrata (Merr. & Chun) P.T.Li Annonaceae >37 (FcB1) 149 Octadeca-9,11,13-triynoic acid Polyalthia cerasoides (Roxb.) Bedd. Annonaceae 18.4 (K1) 150 N-methylouregidione Pseuduvaria setosa (King) J. Sinclair. Annonaceae >50 (K1) 164 Ouregidione Pseuduvaria setosa (King) J. Sinclair. Annonaceae >50 (K1) 164 Oxostephanine Pseuduvaria setosa (King) J. Sinclair. Annonaceae >50 (K1) 164 Ellipticine Aspidosperma vargasii A.DC. Apocynaceae >50 (K1) 49 Aspidosperma desmanthum Benth. Aspidocarpine Aspidosperma vargasii A.DC. Apocynaceae 19 (K1) 49 Aspidosperma desmanthum Benth. Integerrimide A Jatropha integerrima Jacq. Euphorbiaceae >50 (K1) 165 Integerrimide A Jatropha integerrima Jacq. Euphorbiaceae >50 (K1) 165 (-)-Phoebescortechiniine Phoebe scortechinii (Gamb.) Kochummen Lauraceae Nt 166 Phoebegrandine A Phoebe scortechinii (Gamb.) Kochummen LauraceaeAlkaloidal extract = 166 Phoebegrandine B Phoebe scortechinii (Gamb.) Kochummen Lauraceae6.11 g/ml (Gombak A) 166 Tetrahydropronuciferine Phoebe scortechinii (Gamb.) Kochummen Lauraceae0.69 g/ml (D10) 166 Cassiarin B Cassia siamea Lam. Leguminosae 22.0 144 10-Epi-tazopsine Strychnopsis thouarsii Baill. Menispermaceae 16.1 (P. yoelii) 147 Tetrahydropalmatine Stephania rotunda Lour. Menispermaceae 32.6 (W2) 148 Xylopinine Stephania rotunda Lour. Menispermaceae >50 (W2) 148 Cycleanine N-oxide Epinetrum villosum (Exell) Troupin Menispermaceae 13.5 (FcB1) 167 Epimethoxynaucleaorine Nauclea orientalis (L.) L. Rubiaceae 12.4 (D6) 112 13.2 (W2) Naucleofficine B Nauclea officinalis Pierre ex Pitard Rubiaceae 42.1 (FCC1-HN) 157 Naucleofficine C Nauclea officinalis Pierre ex Pitard Rubiaceae 40.5 (FCC1-HN) 157 Naucleofficine D Nauclea officinalis Pierre ex Pitard Rubiaceae 39.8 (FCC1-HN) 157 Naucleofficine E Nauclea officinalis Pierre ex Pitard Rubiaceae 38.3 (FCC1-HN) 157 Uncarine D Mitragyna inermis (Willd.) Kuntze Rubiaceae 46.2 (W2) 168 Maculosidine Vepris uguenensis Engl. Rutaceae >50 (3D7/FCM29) 65 Flindersiamine Esenbeckia febrifuga A.Juss. Rutaceae >50 (3D7/W2) 169 r-Fagarine Esenbeckia febrifuga A.Juss. Rutaceae >50 (3D7/W2) 169 Rutaevine Esenbeckia febrifuga A.Juss. Rutaceae >50 (3D7/W2) 169 Tegerrardin A Teclea gerrardii Verdoorn Rutaceae 12.3 (D10) 170 Dihydroavicine Zanthoxylum rhoifolium Lam. Rutaceae 33.0 (FcB1) 145 Fagaridine Zanthoxylum rhoifolium Lam. Rutaceae 38.0 (FcB1) 145 7,9-Dimethoxy-2,3- Zanthoxylum rubescens Planch. ex Hook. Rutaceae >50 (3D7/FCM29) 171 methylenedioxybenzophenanthridine Bis[6-(5,6-dihydrochelerythrinyl)] ether Zanthoxylum rubescens Planch. ex Hook. Rutaceae 15.3 (3D7) 171 14.9 (FCM29) Zanthomamide Zanthoxylum rubescens Planch. ex Hook. Rutaceae >50 (3D7/FCM29) 171 Lemairamide Zanthoxylum rubescens Planch. ex Hook. Rutaceae >50 (3D7/FCM29) 171 Harmine Peganum harmala L. Zygophyllaceae 37.7 172 Harmaline Peganum harmala L. Zygophyllaceae >50 172

Figure 17 shows other N-containing compounds with compound, 1-(26-hydroxyhexacosanoyl)-glycerol (296). moderate or promising activity in vitro against various strains They showed activity with IC50 values of 5.1 and 9.5 mM [45] of P. falciparum. against D6 and 4.5 and 12.7 mM against W2 strains. Table 4 gives the tested alkaloids presenting low or Crypthophilic acid C (297) isolated from the resin of no activity in vitro against various strains of P. falci- Scrophularia cryptophilla Boiss. & Heldr. (Scrophularia- parum.[49,65,112,144,145,147–150,157,164–172] ceae) showed antimalarial activity with an IC50 of [140] 4.1 mM. Three new ether diglycosides (298–300), namely matayosides A–B and D, were isolated from the Other metabolites root bark of Matayba guianensis Aubl. (Sapindaceae), Two compounds were isolated from the stems and leaves of a plant exhibiting antiplasmodial activity. These compounds Croton lobatus L. (Euphorbiaceae), a medicinal plant used were evaluated for their antiplasmodial activity against [173] in western Africa in traditional folk medicine to cure FcB1 with IC50 values of 8.1, 4.7 and 3.5 mM. malaria, pregnancy troubles and dysentery. (Z,Z,Z)-9,12,15- Guieranone A (301), a naphthyl butenone, was purified Octadecatrienoic acid methyl ester (293) and 8,11,17,21- from the leaves and roots of Guiera senegalensis J. F. Gmel. tetramethyl-(E,E,E,E)-8,10,17,21-tetraentetracosanoic acid (Combretaceae). Guieranone A showed notable antiplasmo- (294) showed some antiplasmodial activity on K1 strain, dial activity (IC50 = 4.1 mM) associated with high cytotoxi- [174] with IC50 values of 10.9 and 9.1 mM, respectively, and SI city towards human monocytes. From the petroleum values of 18.4 and over 20, respectively.[57] Bioassay- ether extract of the root bark of Cussonia zimmermannii directed fractionation of the CHCl3 extract of the dried Harms (Arialaceae), two polyacetylenes were isolated, stems of Rourea minor (Gaertn.) Aubl. (Connoraceae) liana 8-hydroxyheptadeca-1-ene-4,6-diyn-3-yl ethanoate (302) and led to the isolation of rouremin (295), as well as a known 16-acetoxy-11-hydroxyoctadeca-17-ene-12,14-diynyleth-

COOCH3 293 294 COOCH3 O OH HO O O O O O O O 297 O 295 HO O HO O O NH2 OH HO O OH OH O HO OH HO O O O O 296 HO O OH HO OH O OH OH 5 5 5 COOH 298. R1 H, R2 H, R3 (CH2 )14CH3 O O O O 5 5 5 R3 299. R1 Ac, R2 H, R3 CH3 301 300. R 5 H, R 5 H, R 5 CH O 1 2 3 3 O O O R1O O R O 2 O OH OH O O O O O O O 302 O 303 O O O O O

Figure 18 Other metabolites with moderate or promising activity in vitro against various strains of P. falciparum

Table 5 Other metabolites presenting low or no activity in vitro against various strains of P. falciparum

Compound Plant Family IC50 (mM) Reference no.

19-(2-Furyl)nonadeca-5,7-diynoic acid Polyalthia evecta Finet & Gagnep. Annonaceae >50 (K1) 176 8-Hydroxyheptadeca-4,6-diyn-3-yl ethanoate Cussonia zimmermannii Harms Arialaceae 19 175 Scleropyric acid Scleropyrum wallichianum Arn. Santalaceae 27.3 (K1) 177 Matayoside C Matayba guianensis Aubl. Sapindaceae 11.7 (FcB1) 173 anoate (303). They were active with IC50 values of 1.4 and disease. This review focused on publications from 2005 to [175] 2.2 mM, respectively. the end of 2008, and shows that the ethnopharmacological Figure 18 shows other metabolites with moderate or and bio-guided fractionation approaches have led to the promising activity in vitro against various strains of isolation of some promising new antimalarial compounds P. falciparum. with a large variety of structures. About 480 compounds Table 5 gives the tested other metabolites presenting were isolated and evaluated for antimalarial activity in vitro. low or no activity in vitro against various strains of These compounds possess low (11 < IC50 £ 50 mM), mod- [173,175–177] P. falciparum. erate (2 < IC50 £ 11 mM)orpromising(IC50£ 2 mM) activity in vitro against various strains of P. falciparum, which is responsible for the most severe cases of malaria. Discussion Some of the active compounds were also tested for their Several plants are used in traditional medicine in many cytotoxicity but only a few of them were tested for their countries for the treatment of malaria or symptoms of the antimalarial activity in vivo. Nevertheless, in these cases, the

High activity 45 Moderate activity

20 Number of compounds

0 Tannins Lignans Steroids Stilbenes Alkaloids Quinones Coumarins Flavonoids Xanthones derivatives Diterpenes Triterpenes Other phenolic Sesquiterpenes Other metabolites Chemical class

Figure 19 Number of compounds with high (IC50 £ 2 mM) or moderate (2 < IC50 £ 11 mM) activity in vitro against various strains of P. falciparum, classified according to their chemical classes

High activity Moderate activity

10 Number of compounds

0 Vitaceae Tiliaceae Rutaceae Buxaceae Violaceae Moraceae Meliaceae Lauraceae Rubiaceae Clusiaceae Arialaceae Lamiaceae Ebenaceae Lythraceae Piperaceae Ochnaceae Asteraceae Cyperaceae Primulaceae Annonaceae Sapindaceae Celastraceae Rhamnaceae Ginkgoaceae Connaraceae Apocynaceae Leguminosae Cannabaceae Cupressaceae Buddlejaceae Polygonaceae Zingiberaceae Cucurbitaceae Flacourtiaceae Combretaceae Anacardiaceae Magnioliaceae Euphorbiaceae Asphodelaceae Asclepiadaceae Amaryllidaceae Simaroubaceae Caesalpiniaceae Aristolochiaceae Menispermaceae Scrophulariaceae Ancistrocladaceae Plant family

Figure 20 Number of compounds with high (IC50 £ 2 mM) or moderate (2 < IC50 £ 11 mM) activity in vitro against various strains of P. falciparum, classified according to the plant family from which they were isolated

Author Copy: This article was published by the Pharmaceutical Press, which has granted the author permission to distribute this material for personal or professional (non-commercial) use only, subject to the terms and conditions of the Pharmaceutical Press Licence to Publish. Any substantial or systematic reproduction, re-distribution, re-selling, sub-licensing or modification of the whole or part of the article in any form is expressly forbidden. Antimalarial plant compounds Joanne Bero et al. 1429 in vitro against various strains of P. falciparum classified way to find plant metabolites that could be used as templates according to their chemical classes and according to the plant for designing new derivatives with improved properties. family from which they were isolated, respectively. The majority of active diterpenes were isolated from the Caesalpinaceae family and particularly from Caesalipina crista Declarations L. This plant should be further investigated and its several active cassane- and norcassane-compounds tested clinically. Conflict of interest There are different sources of alkaloids that have strong Michel Fre´de´rich is a senior research associate from the activity, Leguminosae, Apocynaceae, Menispermaceae and FNRS. Annonaceae. Leguminosae is one of the greatest families with active alkaloids and flavonoids. The main active Funding alkaloids were derivatives from phenylalanine and tyrosine. Sesquiterpene lactones, like the famous artemisinin from This review received no specific grant from any funding Artemisia annua, have been isolated from a few plants of the agency in the public, commercial or not-for-profit sectors. Asteraceae family but most of them are also highly cytotoxic. Clusiaceae is an interesting plant family which has allowed the isolation of active quinones and xanthones. A review that References covers antimalarial plant metabolites from 1990 to 2000 1. Phillipson JD. Natural products as drugs. Trans R Soc Trop Med highlighted the importance of this family with five new Hyg 1994; 88: 17–19. active xanthones.[3] 2. Fournet A, Munoz V. Natural products as trypanocidal, Moraceae is a family with several interesting compounds antileishmanial and antimalarial drugs. Curr Top Med Chem and particularly flavonoids from A. champeden Spreng. In 2002; 2: 1215–1238. earlier years, active stilbenes were isolated from Artocarpus 3. Schwikkard S, van Heerden FR. Antimalarial activity of plant integer.[3] When examining the structures of the most active metabolites. Nat Prod Rep 2002; 19: 675–692. flavonoids from the last four years, we observed that most of 4. Caniato R, Puricelli L. Review: natural antimalarial agents (1995–2001). Crit Rev Plant Sci 2003; 22: 79–105. them are prenylated compounds, thus being generally more 5. Saxena S et al. Antimalarial agents from plant sources. Curr Sci lipophilic than non-prenylated ones. This higher lipophilicity 2003; 85: 1314–1329. probably increases the resorption through cell membrane, 6. Wright CW. Plant derived antimalarial agents: new leads and which may explain the higher activity often observed. challenges. Phytochem Rev 2005; 4: 55–61. Moreover, common dietary flavonoids possess antimalarial 7. Bilia AR. Non-nitrogenous plant-derived constituents with [180] activity with IC50 values of between 11 and 66 mM. antiplasmodial activity. Nat Prod Commun 2006; 1: 1181–1204. From the 1990s, the major compounds that showed 8. Mambu L, Grellier P. Antimalarial compounds from tradition- promising activity were alkaloids from Apocynaceae and ally used medicinal plants. In: Colegate SM, Molyneux RJ, eds. Loganiaceae, flavonoids from Fabaceae, quinones from Bioactive Natural Products. Detection, Isolation and Structural Asphodelaceae, tannins and triterpenes from Combretaceae Determination, 2nd edn. Boca Raton, USA: CRC press, 2008: [2] 491–529. and butenolides from Monimiaceae. In 2003, a review 9. Kaur K et al. Antimalarials from nature. Bioorg Med Chem showed that three classes of secondary plant metabolites 2009; 17: 3229–3256. were mostly responsible for antimalarial activity: alkaloids, 10. Ramanandralbe V et al. Antiplasmodial phenolic compounds [5] quassinoids and sesquiterpenes lactones. Indeed, non- from Piptadenia pervillei. Planta Med 2008; 74: 417–421. nitrogenous natural products were also shown to be 11. Boonphong S et al. Bioactive compounds from Bauhinia promising.[7] In the present study, very active alkaloids and purpurea possessing antimalarial, antimycobacterial, antifun- quinones were also isolated from Apocynaceae and Aspho- gal, anti-inflammatory, and cytotoxic activities. J Nat Prod 2007; 70: 795–801. delaceae families, respectively, showing the potential of 0 0 these families, but other families must not be underestimated 12. Joseph CC et al. A novel antiplasmodial 3 ,5 -diformylchal- and are also worthy of evaluation. cone and other constituents of Friesodielsia obovata. Nat Prod Res 2007; 21: 1009–1015. In traditional medicine, essential oils containing mono- 13. Namdaung U et al. Bioactive constituents of the root bark of and sesquiterpenes are also used as antimalarials. Several Artocarpus rigidus subsp. rigidus. Chem Pharm Bull 2006; 54: studies showed the antimalarial activity of these oils from 1433–1436. different plant species. For example, the essential oil of 14. Widyawaruyanti A et al. New prenylated flavones from Salvia repens exhibited an IC50 of 1.7 mg/ml with b- Artocarpus champeden, and their antimalarial activity in vitro. phellandrene, b-caryophyllene, limonene and camphor as J Nat Med 2007; 61: 410–413. major components.[181] Nevertheless, the effect of isolated 15. Boonphong S et al. Antitubercular and antiplasmodial compounds was not evaluated and so they are not listed here. prenylated flavones from the roots of Artocarpus altilis. Chiang Mai J Sci 2007; 34: 339–344. 16. Khaomek P et al. In vitro antimalarial activity of prenylated Conclusions flavonoids from Erythrina fusca. J Nat Med 2008; 62: 217–220. 17. Andayi AW et al. Antiplasmodial flavonoids from Erythrina A large number of antimalarial compounds with a wide sacleuxii. Planta Med 2006; 72: 187–189. variety of structures have been isolated from plants and can 18. Rukachaisirikul T et al. Biological activities of the chemical play a role in the development of new antimalarial drugs. constituents of Erythrina stricta and Erythrina subumbrans. Ethnopharmacological approach appears to be a promising Arch Pharm Res 2007; 30: 1398–1403.

19. Rukachaisirikul T et al. Erythrina alkaloids and a pterocarpan 42. Subeki S et al. Anti-babesial and anti-plasmodial compounds from the bark of Erythrina subumbrans. J Nat Prod 2008; 71: from Phyllanthus niruri. J Nat Prod 2005; 68: 537–539. 156–158. 43. Andrade-Neto VF et al. Antiplasmodial activity of aryltetra- 20. Radwan MM et al. Non-cannabinoid constituents from a high lone lignans from Holostylis reniformis. Antimicrob Agents potency Cannabis sativa variety. Phytochemistry 2008; 69: Chemother 2007; 51: 2346–2350. 2627–2633. 44. da Silva AA et al. In vitro antileishmanial and antimalarial 21. Ichino C et al. Antimalarial activity of biflavonoids from activities of tetrahydrofuran lignans isolated from Nectandra Ochna integerrima. Planta Med 2006; 72: 611–614. megapotamica (Lauraceae). Phytother Res 2008; 22: 1307–1310. 22. Weniger B et al. A bioactive biflavonoid from Campnosperma 45. He ZD et al. Rourinoside and rouremin, antimalarial panamense. Fitoterapia 2004; 75: 764–767. constituents from Rourea minor. Phytochemistry 2006; 67: 23. Weniger B et al. Comparative antiplasmodial, leishmanicidal 1378–1384. and antitrypanosomal activities of several biflavonoids. 46. Reddy MK et al. Antioxidant, antimalarial and antimicrobial Phytomedicine 2006; 13: 176–180. activities of tannin-rich fractions, ellagitannins and phenolic 24. Mbwambo ZH et al. Antiparasitic activity of some xanthones acids from Punica granatum L. Planta Med 2007; 73: 461– and biflavonoids from the root bark of Garcinia livingstonei. 467. J Nat Prod 2006; 69: 369–372. 47. Lee SJ et al. Bioassay-guided isolation of antiplasmodial 25. Midiwo JO et al. The first 9-hydroxyhomoisoflavanone, and anacardic acids derivatives from the whole plants of Viola antiplasmodial chalcones, from the aerial exudates of Poly- websteri Hemsl. Parasitol Res 2009; 104: 463–466. gonum senegalense. Arkivoc 2007; ix: 21–27. 48. Vega AS et al. Antimalarials and antioxidants compounds 26. Portet B et al. Activity-guided isolation of antiplasmodial from Piper tricuspe (Piperaceae). Pharmacologyonline 2008; dihydrochalcones and flavanones from Piper hostmannianum 1: 1–8. var. berbicense. Phytochemistry 2007; 68: 1312–1320. 49. Andrade-Neto VF et al. In vitro inhibition of Plasmodium 27. Narender T et al. Prenylated chalcones isolated from falciparum by substances isolated from Amazonian antimalar- Crotalaria genus inhibits in vitro growth of the human malaria ial plants. Mem Inst Oswaldo Cruz 2007; 102: 359–365. parasite Plasmodium falciparum. Bioorg Med Chem Lett 2005; 50. Oshimi S et al. Chrobisiamone A, a new bischromone from 15: 2453–2455. Cassia siamea and a biomimetic transformation of 5-acetonyl- 28. Ngameni B et al. Antimalarial prenylated chalcones from the 7-hydroxy-2-methylchromone into cassiarin A. Bioorg Med twigs of Dorstenia barteri var. subtriangularis. Arkivoc 2007; Chem Lett 2008; 18: 3761–3763. xiii: 116–123. 51. Ahmed SA et al. Structure determination and absolute 29. Argotte-Ramos R et al. Antimalarial 4-phenylcoumarins from configuration of cannabichromanone derivatives from high thestembarkofHintonia latiflora. J Nat Prod 2006; 69: 1442– potency Cannabis sativa. Tetrahedron Lett 2008; 49: 6050– 1444. 6053. 30. Azebaze AGB et al. Prenylated xanthone derivatives with 52. Wirasathien L et al. Cytotoxic C-benzylated chalcone and antiplasmodial activity from Allanblackia monticola Staner other constituents of Ellipeiopsis cherrevensis. Arch Pharm LC. Chem Pharm Bull 2006; 54: 111–113. Res 2006; 29: 497–502. 31. Azebaze AGB et al. Antimalarial and vasorelaxant constitu- 53. Abbas FA et al. Phytochemical and biological studies on Saudi ents of the leaves of Allanblackia monticola (Guttiferae). Ann Commiphora opobalsamum L. Nat Prod Res 2007; 21: 383– Trop Med Parasitol 2007; 101: 23–30. 391. 32. Laphookhieo S et al. Cytotoxic and antimalarial prenylated 54. Molinar-Toribio E et al. Antiprotozoal activity against xanthones from Cratoxylum cochinchinense. Chem Pharm Plasmodium falciparum and Trypanosoma cruzi of xanthones Bull 2006; 54: 745–747. isolated from Chrysochlamys tenuis. Pharm Biol 2006; 44: 33. Ngouela S et al. Anti-plasmodial and antioxidant activities of 550–553. constituents of the seed shells of Symphonia globulifera Linn f. 55. Vongvanich N et al. Combretastatins D-3 and D-4 new Phytochemistry 2006; 67: 302–306. macrocyclic lactones from Getonia floribunda. Planta Med 34. Karan M et al. Phytochemical and antimalarial studies on 2005; 71: 191–193. Swertia alata Royale. Acta Hortic 2005; 675: 139–145. 56. Cao SG et al. Antiplasmodial activity of compounds from 35. Lannang AM et al. Antimalarial compounds from the root Sloanea rhodantha (Baker) Capuron var. rhodantha from the bark of Garcinia polyantha Olv. J Antibiot 2008; 61: Madagascar rain forest. Planta Med 2006; 72: 1438–1440. 518–523. 57. Attioua B et al. Antiplasmodial activity of constituents isolated 36. Son IH et al. Antiplasmodial activity of novel stilbene from Croton lobatus. Pharm Biol 2007; 45: 263–266. derivatives isolated from Parthenocissus tricuspidata from 58. van Baren C et al. Triterpenic acids and flavonoids from South Korea. Parasitol Res 2007; 101: 237–241. Satureja parvifolia. Evaluation of their antiprotozoal activity. 37. Park WH et al. Antimalarial activity of a new stilbene Z Naturforsch C 2006; 61: 189–192. glycoside from Parthenocissus tricuspidata in mice. Anti- 59. Radwan MM. Isoflavonoids from an Egyptian collection of microb Agents Chemother 2008; 52: 3451–3453. Colutea istria. Nat Prod Commun 2008; 3: 1491–1494. 38. Lee SI et al. Antimalarial activity of a stilbene glycoside from 60. Kapingu MC et al. A novel isoflavonoid from Millettia Pleuropterus ciliinervis. Ann Trop Med Parasitol 2008; 102: puguensis. Planta Med 2006; 72: 1341–1343. 181–184. 61. Abrantes M et al. Antiplasmodial activity of lignans and 39. Moon HI, Sim J. Antimalarial activity in mice of resveratrol extracts from Pycnanthus angolensis. Planta Med 2008; 74: derivative from Pleuropterus ciliinervis. AnnTropMed 1408–1412. Parasitol 2008; 102: 447–450. 62. Torres-Mendoza D et al. Weakly antimalarial flavonol 40. Ross SA et al. Constituents of Zanthoxylum flavum and their arabinofuranosides from Calycolpus warszewiczianus. J Nat antioxidant and antimalarial activities. Nat Prod Commun Prod 2006; 69: 826–828. 2008; 3: 791–794. 63. Cimanga RK et al. Antimalarial activity of some extracts and 41. Ma CY et al. Antimalarial compounds from Grewia isolated constituents from Morinda morindoides leaves. J Nat bilamellata. J Nat Prod 2006; 69: 346–350. Remedies 2008; 8: 191–202.

64. Carroll AR et al. Prenylated dihydrochalcones from Boronia 86. Chung IM et al. Antiplasmodial activity of sesquiterpene bipinnata that inhibit the malarial parasite enzyme target lactone from Carpesium rosulatum in mice. Parasitol Res hemoglobinase II. J Nat Prod 2008; 71: 1479–1480. 2008; 103: 341–344. 65. Cheplogoi PK et al. An azole, an amide and a limonoid from 87. Karioti A et al. Inhibiting enoyl-ACP reductase (FabI) across Vepris uguenensis (Rutaceae). Phytochemistry 2008; 69: pathogenic microorganisms by linear sesquiterpene lactones 1384–1388. from Anthemis auriculata. Phytomedicine 2008; 15: 1125–1129. 66. Tuntiwachwuttikul P et al. Chromones from the branches of 88. Adelekan AM et al. Bioactive diterpenes and other constituents Harrisonda perforata. Chem Pharm Bull 2006; 54: 44–47. of Croton steenkampianus. J Nat Prod 2008; 71: 1919–1922. 67. Tasdemir D et al. Antituberculotic and antiprotozoal activities 89. Kenmogne M et al. Five labdane diterpenoids from the of primin, a natural benzoquinone: in vitro and in vivo studies. seeds of Aframomum zambesiacum. Phytochemistry 2006; 67: Chem Biodivers 2006; 3: 1230–1237. 433–438. 68. Moein MR et al. Antileishmanial, antiplasmodial and 90. Okasaka M et al. Terpenoids from Juniperus polycarpus var. cytotoxic activities of 12,16-dideoxy aegyptinone B from seravschanica. Phytochemistry 2006; 67: 2635–2640. Zhumeria majdae Rech.f. & Wendelbo. Phytother Res 2008; 91. Nyiligira E et al. Phytochemistry and in vitro pharmacological 22: 283–285. activities of South African Vitex (Verbenaceae) species. J 69. Mutanyatta J et al. The first 60-O-sulfated phenylanthraqui- Ethnopharmacol 2008; 119: 680–685. nones: isolation from Bulbine frutescens, structural elucida- 92. Jullian V et al. New clerodane diterpenoids from Laetia tion, enantiomeric purity, and partial synthesis. Tetrahedron procera (Poepp. ) Eichler (Flacourtiaceae), with antiplasmo- 2005; 61: 8475–8484. dial and antileishmanial activities. Bioorg Med Chem Lett 70. Bringmann G et al. Joziknipholones A and B: the first dimeric 2005; 15: 5065–5070. phenylanthraquinones, from the roots of Bulbine frutescens. 93. Kanokmedhakul S et al. New bioactive clerodane diterpenoids Chemistry 2008; 14: 1420–1429. from the bark of Casearia grewiifolia. J Nat Prod 2005; 68: 71. Wube AA et al. Antimalarial compounds from Kniphofia 183–188. foliosa roots. Phytother Res 2005; 19: 472–476. 94. Thongnest S et al. Oxygenated pimarane diterpenes from 72. Lenta BN et al. Anti-plasmodial and cholinesterase inhibiting Kaempferia marginata. J Nat Prod 2005; 68: 1632–1636. activities of some constituents of Psorospermum glaberrimum. 95. Linn TZ et al. Cassane- and norcassane-type diterpenes from Chem Pharm Bull 2008; 56: 222–226. Caesalpinia crista of Indonesia and their antimalarial activity 73. Lenta BN et al. Anti-plasmodial activity of some constituents against the growth of Plasmodium falciparum. J Nat Prod of the root bark of Harungana madagascariensis LAM. 2005; 68: 706–710. (Hypericaceae). Chem Pharm Bull 2007; 55: 464–467. 96. Kalauni SK et al. Antimalarial activity of cassane- and 74. Ichino C et al. Screening of Thai medicinal plant extracts and norcassane-type diterpenes from Caesalpinia crista and their their active constituents for in vitro antimalarial activity. structure–activity relationship. Biol Pharm Bull 2006; 29: Phytother Res 2006; 20: 307–309. 1050–1052. 75. Eyong KO et al. Newbouldiaquinone A: a naphthoquinone- 97. Awale S et al. Constituents of Caesalpinia crista from anthraquinone ether coupled pigment, as a potential anti- Indonesia. Chem Pharm Bull 2006; 54: 213–218. microbial and antimalarial agent from Newbouldia laevis. 98. Pudhom K et al. Cassane furanoditerpenoids from the seed Phytochemistry 2006; 67: 605–609. kernels of Caesalpinia bonduc from Thailand. J Nat Prod 76. Tuntiwachwuttikul P et al. Anthraquinones from the roots of 2007; 70: 1542–1544. Prismatomeris malayana. Nat Prod Res 2008; 22: 962–968. 99. Matsuno Y et al. Sucutiniranes A and B, new cassane-type 77. Rukunga GM et al. Anti-plasmodial activity of the extracts and diterpenes from Bowdichia nitida. Bioorg Med Chem Lett two sesquiterpenes from Cyperus articulatus. Fitoterapia 2008; 18: 3774–3777. 2008; 79: 188–190. 100. Chukwujekwu JC et al. Antiplasmodial diterpenoid from the 78. Pillay P et al. Isolation and identification of antiplasmodial leaves of Hyptis suaveolens. J Ethnopharmacol 2005; 102: sesquiterpene lactones from Oncosiphon piluliferum. J Ethno- 295–297. pharmacol 2007; 112: 71–76. 101. Van Zyl RL et al. Antiplasmodial activities of some abietane 79. Ramanandraibe V et al. Pseudoguanolide sesquiterpene diterpenes from the leaves of five Plectranthus species. S Afr J lactones from Vernoniopsis caudata and their in vitro anti- Sci 2008; 104: 62–64. plasmodial activities. J Nat Prod 2005; 68: 800–803. 102. Samoylenko V et al. Antiparasitic, nematicidal and antifouling 80. Ortet R et al. Sesquiterpene lactones from the endemic Cape constituents from Juniperus berries. Phytother Res 2008; 22: Verdean Artemisia gorgonum. Phytochemistry 2008; 69: 1570–1576. 2961–2965. 103. Koch A et al. An antimalarial abietane diterpene from 81. That QT et al. Wedelolides A and B: novel sesquiterpene Fuerstia africana TCE fries. Biochem Syst Ecol 2006; 34: delta-lactones, (9R)-eudesman-9,12-olides, from Wedelia 270–272. trilobata. J Org Chem 2007; 72: 7102–7105. 104. Mongkolvisut W, Sutthivaiyakit S. Antimalarial and antitu- 82. Chea A et al. Antimalarial activity of sesquiterpene lactones berculous poly-O-acylated jatrophane diterpenoids from Ped- from Vernonia cinerea. Chem Pharm Bull 2006; 54: 1437– ilanthus tithymaloides. J Nat Prod 2007; 70: 1434–1438. 1439. 105. Murata T et al. Antiplasmodial triterpenoids from Ekebergia 83. Pillay P et al. Antiplasmodial hirsutinolides from Vernonia capensis. J Nat Prod 2008; 71: 167–174. staehelinoides and their utilization towards a simplified 106. Mambu L et al. Clerodane and labdane diterpenoids from pharmacophore. Phytochemistry 2007; 68: 1200–1205. Nuxia sphaerocephala. Phytochemistry 2006; 67: 444–451. 84. Vongvanich N et al. Antiplasmodial, antimycobacterial, and 107. Suksamrarn S et al. Ceanothane- and lupane-type triterpenes cytotoxic principles from Camchaya calcarea. Planta Med with antiplasmodial and antimycobacterial activities from 2006; 72: 1427–1430. Ziziphus cambodiana. Chem Pharm Bull 2006; 54: 535–537. 85. Moon HI. Antiplasmodial activity of ineupatorolides A 108. Ma CY et al. Study of antimalarial activity of chemical from Carpesium rosulatum. Parasitol Res 2007; 100: constituents from Diospyros quaesita. Chem Biodivers 2008; 1147–1149. 5: 2442–2448.

109. Thiem DA et al. Bisnortriterpenes from Salacia madagascar- 133. Akam TM et al. A pregnane derivative and an anti-plasmodial iensis. J Nat Prod 2005; 68: 251–254. labdane diterpenoid from the stem bark of Turraenthus 110. Cimanga RK et al. Bioassay-guided isolation of antimalarial africanus. Nat Prod Commun 2006; 1: 449–452. triterpenoid acids from the leaves of Morinda lucida. Pharm 134. Yin S et al. The first limonoid peroxide in the Meliaceae Biol 2006; 44: 677–681. family: walsuronoid a from Walsura robusta. Org Lett 2007; 9: 111. Moon HI et al. Antiplasmodial activity of triterpenoid isolated 2353–2356. from whole plants of Viola genus from South Korea. Parasitol 135. Flores N et al. Benzoic acid derivatives from Piper species Res 2007; 100: 641–644. and their antiparasitic activity. J Nat Prod 2008; 71: 1538– 112. He ZD et al. Antimalarial constituents from Nauclea orientalis 1543. (L.) L. Chem Biodivers 2005; 2: 1378–1386. 136. Chumkaew P et al. A new triterpenoid ester from the fruits of 113. Banzouzi JT et al. Cogniauxia podolaena: bioassay-guided Bruguiera parviflora. Chem Pharm Bull 2005; 53: 95–96. fractionation of defoliated stems, isolation of active com- 137. Kanokmedhakul K et al. Biological activity of anthraquinones pounds, antiplasmodial activity and cytotoxicity. Planta Med and triterpenoids from Prismatomeris fragrans. J Ethnophar- 2008; 74: 1453–1456. macol 2005; 100: 284–288. 114. Kamatou GPP et al. Antimalarial and anticancer activities of 138. Tasdemir D et al. Anti-protozoal and plasmodial FabI enzyme selected South African Salvia species and isolated compounds inhibiting metabolites of Scrophularia lepidota roots. Phyto- from S. radula. S Afr J Bot 2008; 74: 238–243. chemistry 2005; 66: 355–362. 115. Saewan N et al. Antimalarial tetranortriterpenoids from the 139. Pawar RS et al. Glycosides of 20-deoxy derivatives of seeds of Lansium domesticum Corr. Phytochemistry 2006; 67: jujubogenin and pseudojujubogenin from Bacopa monniera. 2288–2293. Planta Med 2007; 73: 380–383. 116. Lee SE et al. Antimalarial activity of anthothecol derived from 140. Tasdemir D et al. Evaluation of antiprotozoal and antimyco- Khaya anthotheca (Meliaceae). Phytomedicine 2008; 15: 533–535. bacterial activities of the resin glycosides and the other 117. Bickii J et al. The antiplasmodial agents of the stem bark of metabolites of Scrophularia cryptophila. Phytomedicine 2008; Entandrophragma angolense (Meliaceae). Afr J Tradit Com- 15: 209–215. plement Altern Med 2007; 4: 135–139. 141. Rukunga GM et al. The antiplasmodial activity of spermine 118. Maneerata W et al. Antimalarial, antimycobacterial and alkaloids isolated from Albizia gummifera. Fitoterapia 2007; cytotoxic limonoids from Chisocheton siamensis. Phytomedi- 78: 455–459. cine 2008; 15: 1130–1134. 142. Rumalla CS et al. Alkaloids from Heimia salicifolia. 119. Hay AE et al. Limonoid orthoacetates and antiprotozoal Phytochemistry 2008; 69: 1756–1762. compounds from the roots of Pseudocedrela kotschyi. J Nat 143. Toriizuka Y et al. New lycorine-type alkaloid from Lycoris Prod 2007; 70: 9–13. traubii and evaluation of antitrypanosomal and antimalarial 120. Abdel-Sattar E et al. Acylated pregnane glycosides from activities of lycorine derivatives. Bioorg Med Chem 2008; 16: Caralluma tuberculata and their antiparasitic activity. Phy- 10 182–10 189. tochemistry 2008; 69: 2180–2186. 144. Morita H et al. Cassiarins A and B, novel antiplasmodial 121. Fotie J et al. Lupeol long-chain fatty acid esters with alkaloids from Cassia siamea. Org Lett 2007; 9: 3691–3693. antimalarial activity from Holarrhena floribunda. J Nat Prod 145. Jullian V et al. Validation of use of a traditional antimalarial 2006; 69: 62–67. remedy from French Guiana, Zanthoxylum rhoifolium Lam. 122. Lhinhatrakool T, Sutthivaiyakit S. 19-Nor- and 18,20-epoxy- J Ethnopharmacol 2006; 106: 348–352. cardenolides from the leaves of Calotropis gigantea. J Nat 146. Mazier D et al. Alkaloid compounds and their use as Prod 2006; 69: 1249–1251. antimalarial drugs. International Patent Application No. 123. Karioti A et al. Anthecularin: a novel sesquiterpene lactone PCT/EP2005/00523, 21 April 2005. from Anthemis auriculata with antiprotozoal activity. J Org 147. Carraz M et al. Isolation and antimalarial activity of new Chem 2007; 72: 8103–8106. morphinan alkaloids on Plasmodium yoelii liver stage. Bioorg 124. Andrade SF et al. Antileishmanial, antimalarial and anti- Med Chem 2008; 16: 6186–6192. microbial activities of the extract and isolated compounds 148. Chea A et al. Antimalarial activity of alkaloids isolated from Austroplenckia populnea (Celastraceae). Z Naturforsch from Stephania rotunda. J Ethnopharmacol 2007; 112: 132–137. C, J Biosci 2008; 63: 497–502. 149. Nguyen NT et al. Antiplasmodial alkaloids from Desmos 125. Ngouamegne ET et al. Endodesmiadiol, a friedelane triterpe- rostrata. J Nat Prod 2008; 71: 2057–2059. noid, and other antiplasmodial compounds from Endodesmia 150. Kanokmedhakul S et al. Bioactive constituents of the roots of calophylloides. Chem Pharm Bull 2008; 56: 374–377. Polyalthia cerasoides. J Nat Prod 2007; 70: 1536–1538. 126. Fu X et al. Cycloartane glycosides from Sutherlandia 151. Osorio E et al. Actividad antiplasmodial de alcaloides frutescens. J Nat Prod 2008; 71: 1749–1753. aporfinicos de Rollinia pittieri y Pseudomalmea boyacana 127. Agnihotri VK et al. New labdane diterpenes from Leonurus (Annonaceae). Vitae. Rev Fac Quimica Farm 2006; 13: 49–54. cardiaca. Planta Med 2008; 74: 1288–1290. 152. Phrutivorapongkul A et al. Anti-plasmodial activity of 128. Acharya BN et al. Antimalarial activity of Gomphostemma bisbenzylisoquinoline alkaloids from Michelia figo leaves. crinitum leaf extracts. Med Chem Res 2008; 17: 530–540. Thai J Health Res 2006; 20: 121–128. 129. Jonville MC et al. Fagraldehyde, a secoiridoid isolated from 153. Roumy V et al. Isolation and antimalarial activity of alkaloids Fagraea fragrans. J Nat Prod 2008; 71: 2038–2040. from Pseudoxandra cuspidata. Planta Med 2006; 72: 894–898. 130. Lagnika L et al. Phytochemical study and antiprotozoal 154. Murebwayire S et al. Antiplasmodial and antitrypanosomal activity of compounds isolated from Thalia geniculata. activity of Triclisia sacleuxii (Pierre) Diels. Phytomedicine Pharm Biol 2008; 46: 162–165. 2008; 15: 728–733. 131. Traore M et al. Cytotoxic kurubasch aldehyde from Trichilia 155. Bringmann G et al. ent-Dioncophylleine A and related emetica. Nat Prod Res 2007; 21: 13–17. dehydrogenated naphthylisoquinoline alkaloids, the first 132. Ngemenya MN et al. Antiplasmodial activities of some Asian dioncophyllaceae-type alkaloids, from the ‘new’ plant products from Turreanthus africanus (Meliaceae). Afr J Health species Ancistrocladus benomensis. J Nat Prod 2005; 68: 686– Sci 2006; 13: 33–39. 690.

156. Bringmann G et al. Six naphthylisoquinoline alkaloids and a traditionally used to treat malaria in the Brazilian Amazon. related benzopyranone from a Congolese Ancistrocladus Phytomedicine 2008; 15: 367–372. species related to Ancistrocladus congolensis. Phytochemistry 170. Waffo AFK et al. Acridone and furoquinoline alkaloids from 2008; 69: 1065–1075. Teclea gerrardii (Rutaceae: Toddalioideae) of southern Africa. 157. Sun JY et al. Indole alkoloids from Nauclea officinalis with weak Phytochemistry 2007; 68: 663–667. antimalarial activity. Phytochemistry 2008; 69: 1405–1410. 171. Penali L et al. Low antiplasmodial activity of alkaloids and 158. Van Miert S et al. Isoneocryptolepine, a synthetic indoloquino- amides from the stem bark of Zanthoxylum rubescens line alkaloid, as an antiplasmodial lead compound. J Nat Prod (Rutaceae). Parasite 2007; 14: 161–164. 2005; 68: 674–677. 172. Astulla A et al. Alkaloids from the seeds of Peganum harmala 159. Philippe G et al. In vivo antimalarial activity of isosungucine, showing antiplasmodial and vasorelaxant activities. J Nat Med an indolomonoterpenic alkaloid from Strychnos icaja. Planta 2008; 62: 470–472. Med 2007; 73: 478–479. 173. de Mesquita ML et al. New ether diglycosides from Matayba 160. Devkota KP et al. Cholinesterase inhibiting and antiplasmodial guianensis with antiplasmodial activity. Bioorg Med Chem steroidal alkaloids from Sarcococca hookeriana. Chem Pharm 2005; 13: 4499–4506. Bull 2007; 55: 1397–1401. 174. Fiot J et al. Phytochemical and pharmacological study of roots 161. Zirihi GN et al. Isolation, characterization and antiplasmodial and leaves of Guiera senegalensis JF Gmel (Combretaceae). activity of steroidal alkaloids from Funtumia elastica (Preuss) J Ethnopharmacol 2006; 106: 173–178. Stapf. Bioorg Med Chem Lett 2005; 15: 2637–2640. 175. Senn M et al. Antiprotozoal polyacetylenes from the 162. Suksamrarn S et al. Ziziphine N, O, P and Q, new Tanzanian medicinal plant Cussonia zimmermannii. J Nat antiplasmodial cyclopeptide alkaloids from Ziziphus oenoplia Prod 2007; 70: 1565–1569. var. brunoniana. Tetrahedron 2005; 61: 1175–1180. 176. Kanokmedhakul S et al. 2-Substituted furans from the roots of 163. Ross SA et al. Alkamides from the leaves of Zanthoxylum Polyalthia evecta. J Nat Prod 2006; 69: 68–72. syncarpum. J Nat Prod 2005; 68: 1297–1299. 177. Suksamrarn A et al. Antimycobacterial and antiplasmodial 164. Wirasathien L et al. Biological activities of alkaloids from unsaturated carboxylic acid from the twigs of Scleropyrum Pseuduvaria setosa. Pharm Biol 2006; 44: 274–278. wallichianum. Chem Pharm Bull 2005; 53: 1327–1329. 165. Mongkolvisut W et al. Integerrimides A and B, cyclic 178. Bertani S et al. Simalikalactone D is responsible for the heptapeptides from the latex of Jatropha integerrima. J Nat antimalarial properties of an amazonian traditional remedy Prod 2006; 69: 1435–1441. made with Quassia amara L. (Simaroubaceae). J Ethnophar- 166. Awang K et al. New alkaloids from Phoebe scortechinii. Nat macol 2006; 108: 155–157. Prod Res 2007; 21: 704–709. 179. Elford BC et al. Potentiation of the antimalarial activity of 167. Otshudi AL et al. Biologically active bisbenzylisoquinoline ginghaosu by methoxylated flavones. Trans R Soc Trop Med alkaloids from the root bark of Epinetrum villosum. J Hyg 1987; 81: 434–436. Ethnopharmacol 2005; 102: 89–94. 180. Lehane AM, Saliba KJ. Common dietary flavonoids inhibit the 168. Fiot J et al. HPLC quantification of uncarine D and growth of the intraerythrocytic malaria parasite. BMC Res the anti-plasmodialactivityof alkaloids from leaves of Mitragyna Notes 2008; 1: 26 inermis (Willd.) O. Kuntze. Phytochem Anal 2005; 16: 30–33. 181. Kamatou GPP et al. The in vitro pharmacological activities 169. Dolabela MF et al. In vitro antiplasmodial activity of ext- and a chemical investigation of three South African Salvia ract and constituents from Esenbeckia febrifuga, a plant species. J Ethnopharmacol 2005; 102: 382–390.